annonars 0.42.0

//! Implementation of endpoint `/api/v1/seqvars/annos`.
//!
//! Also includes the implementation of the `/annos/variant` endpoint (deprecated).

use actix_web::{
    get,
    web::{self, Data, Json, Path},
};
use strum::IntoEnumIterator;

use crate::{
    common::{keys, version},
    server::run::{fetch::fetch_pos_protobuf, AnnoDb},
};

use super::error::CustomError;
use super::fetch::{
    fetch_pos_protobuf_json, fetch_var_protobuf, fetch_var_protobuf_json, fetch_var_tsv_json,
};

/// Parameters for `variant_annos::handle`.
///
/// Defines a variant in VCF-style format with a genome release specification.
#[serde_with::skip_serializing_none]
#[serde_with::serde_as]
#[derive(
    Debug, Clone, serde::Serialize, serde::Deserialize, utoipa::ToSchema, utoipa::IntoParams,
)]
pub struct SeqvarsAnnosQuery {
    /// Genome release specification.
    pub genome_release: String,
    /// Chromosome name.
    pub chromosome: String,
    /// 1-based position for VCF-style variant.
    pub pos: u32,
    /// Reference allele bases.
    pub reference: String,
    /// Alterantive allele bases.
    pub alternative: String,
}

impl From<SeqvarsAnnosQuery> for keys::Var {
    fn from(value: SeqvarsAnnosQuery) -> Self {
        keys::Var {
            chrom: value.chromosome,
            pos: value.pos as i32,
            reference: value.reference,
            alternative: value.alternative,
        }
    }
}

impl From<SeqvarsAnnosQuery> for keys::Pos {
    fn from(value: SeqvarsAnnosQuery) -> Self {
        keys::Pos {
            chrom: value.chromosome,
            pos: value.pos as i32,
        }
    }
}

/// Result for `handle`.
#[derive(Debug, Clone, serde::Serialize, serde::Deserialize, utoipa::ToSchema)]
#[serde_with::skip_serializing_none]
struct Container {
    /// Version of the server code.
    pub server_version: String,
    /// The query parameters.
    pub query: SeqvarsAnnosQuery,
    /// Annotations for the variant from each database.
    pub result: std::collections::BTreeMap<AnnoDb, Option<serde_json::Value>>,
}

/// Query for annotations for one variant.
#[get("/annos/variant")]
async fn handle(
    data: Data<crate::server::run::WebServerData>,
    _path: Path<()>,
    query: web::Query<SeqvarsAnnosQuery>,
) -> actix_web::Result<Json<Container>, CustomError> {
    let genome_release =
        query
            .clone()
            .into_inner()
            .genome_release
            .parse()
            .map_err(|e: strum::ParseError| {
                CustomError::new(anyhow::anyhow!("problem getting genome release: {}", e))
            })?;

    let mut annotations = std::collections::BTreeMap::default();
    for anno_db in AnnoDb::iter() {
        match anno_db {
            AnnoDb::Other => (),
            AnnoDb::Clinvar => {
                data.annos[genome_release][anno_db]
                    .as_ref()
                    .map(|db| {
                        fetch_var_protobuf_json::<
                            crate::pbs::clinvar::minimal::ExtractedVcvRecordList,
                        >(
                            &db.data,
                            anno_db.cf_name(),
                            query.clone().into_inner().into(),
                        )
                    })
                    .transpose()?
                    .map(|v| annotations.insert(anno_db, v));
            }
            AnnoDb::Cadd | AnnoDb::Dbnsfp | AnnoDb::Dbscsnv => {
                data.annos[genome_release][anno_db]
                    .as_ref()
                    .map(|db| {
                        fetch_var_tsv_json(
                            &db.data,
                            anno_db.cf_name(),
                            query.clone().into_inner().into(),
                        )
                    })
                    .transpose()?
                    .map(|v| annotations.insert(anno_db, v));
            }
            AnnoDb::Dbsnp => {
                data.annos[genome_release][anno_db]
                    .as_ref()
                    .map(|db| {
                        fetch_var_protobuf_json::<crate::dbsnp::pbs::Record>(
                            &db.data,
                            anno_db.cf_name(),
                            query.clone().into_inner().into(),
                        )
                    })
                    .transpose()?
                    .map(|v| annotations.insert(anno_db, v));
            }
            AnnoDb::Helixmtdb => {
                data.annos[genome_release][anno_db]
                    .as_ref()
                    .map(|db| {
                        fetch_var_protobuf_json::<crate::helixmtdb::pbs::Record>(
                            &db.data,
                            anno_db.cf_name(),
                            query.clone().into_inner().into(),
                        )
                    })
                    .transpose()?
                    .map(|v| annotations.insert(anno_db, v));
            }
            AnnoDb::GnomadMtdna => {
                data.annos[genome_release][anno_db]
                    .as_ref()
                    .map(|db| {
                        fetch_var_protobuf_json::<crate::pbs::gnomad::mtdna::Record>(
                            &db.data,
                            anno_db.cf_name(),
                            query.clone().into_inner().into(),
                        )
                    })
                    .transpose()?
                    .map(|v| annotations.insert(anno_db, v));
            }
            AnnoDb::GnomadExomes => {
                data.annos[genome_release][anno_db]
                    .as_ref()
                    .map(|db| {
                        let db_version = data.db_infos[genome_release][anno_db]
                            .as_ref()
                            .expect("must have db info here")
                            .db_version
                            .as_ref()
                            .expect("gnomAD must have db version");

                        if db_version.starts_with("2.") {
                            fetch_var_protobuf_json::<crate::pbs::gnomad::gnomad2::Record>(
                                &db.data,
                                anno_db.cf_name(),
                                query.clone().into_inner().into(),
                            )
                        } else if db_version.starts_with("4.") {
                            fetch_var_protobuf_json::<crate::pbs::gnomad::gnomad4::Record>(
                                &db.data,
                                anno_db.cf_name(),
                                query.clone().into_inner().into(),
                            )
                        } else {
                            Err(CustomError::new(anyhow::anyhow!(
                                "don't know how to handle gnomAD version {}",
                                db_version
                            )))
                        }
                    })
                    .transpose()?
                    .map(|v| annotations.insert(anno_db, v));
            }
            AnnoDb::GnomadGenomes => {
                data.annos[genome_release][anno_db]
                    .as_ref()
                    .map(|db| {
                        let db_version = data.db_infos[genome_release][anno_db]
                            .as_ref()
                            .expect("must have db info here")
                            .db_version
                            .as_ref()
                            .expect("gnomAD must have db version");
                        if db_version.starts_with("2.") {
                            fetch_var_protobuf_json::<crate::pbs::gnomad::gnomad2::Record>(
                                &db.data,
                                anno_db.cf_name(),
                                query.clone().into_inner().into(),
                            )
                        } else if db_version.starts_with("3.") {
                            fetch_var_protobuf_json::<crate::pbs::gnomad::gnomad3::Record>(
                                &db.data,
                                anno_db.cf_name(),
                                query.clone().into_inner().into(),
                            )
                        } else if db_version.starts_with("4.") {
                            fetch_var_protobuf_json::<crate::pbs::gnomad::gnomad4::Record>(
                                &db.data,
                                anno_db.cf_name(),
                                query.clone().into_inner().into(),
                            )
                        } else {
                            Err(CustomError::new(anyhow::anyhow!(
                                "don't know how to handle gnomAD version {}",
                                db_version
                            )))
                        }
                    })
                    .transpose()?
                    .map(|v| annotations.insert(anno_db, v));
            }
            AnnoDb::UcscConservation => {
                data.annos[genome_release][anno_db]
                    .as_ref()
                    .map(|db| {
                        let start: keys::Pos = query.clone().into_inner().into();
                        let start = keys::Pos {
                            chrom: start.chrom,
                            pos: start.pos - 2,
                        };
                        let stop = query.clone().into_inner().into();
                        fetch_pos_protobuf_json::<crate::pbs::cons::RecordList>(
                            &db.data,
                            anno_db.cf_name(),
                            start,
                            stop,
                        )
                    })
                    .transpose()?
                    .map(|v| annotations.insert(anno_db, v));
            }
        }
    }

    let result = Container {
        server_version: version().to_string(),
        query: query.into_inner(),
        result: annotations,
    };

    Ok(Json(result))
}

/// `SeqvarsAnnosResponse` and related types.
pub mod response {
    use crate::{pbs, server::run::clinvar_data::ClinvarExtractedVcvRecord};

    /// Protocol buffer for `Vep.domains`
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct VepCommonDomain {
        /// Domain ID.
        pub id: String,
        /// Domain source.
        pub source: String,
    }

    impl From<pbs::gnomad::vep_common::Domain> for VepCommonDomain {
        fn from(value: pbs::gnomad::vep_common::Domain) -> Self {
            VepCommonDomain {
                id: value.id,
                source: value.source,
            }
        }
    }

    /// Store the scoring of a prediction.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct VepCommonPrediction {
        /// Prediction.
        pub prediction: String,
        /// Score.
        pub score: f32,
    }

    impl From<pbs::gnomad::vep_common::Prediction> for VepCommonPrediction {
        fn from(value: pbs::gnomad::vep_common::Prediction) -> Self {
            VepCommonPrediction {
                prediction: value.prediction,
                score: value.score,
            }
        }
    }

    /// Protocol buffer for the gnomAD-mtDNA VEP predictions.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad2Vep {
        /// Allele of record.
        pub allele: String,
        /// Consequence, e.g., `"missense_variant"`.
        pub consequence: String,
        /// Impact, e.g., `"MODERATE"`.
        pub impact: String,
        /// Gene symbol, e.g., `"PCSK9"`.
        pub symbol: String,
        /// Gene ID, `e.g., "ENSG00000169174"`.
        pub gene: String,
        /// Feature type, e.g., `"Transcript"`.
        pub feature_type: String,
        /// Feature ID, e.g., `"ENST00000302118"`.
        pub feature: String,
        /// Feature biotype, e.g., `"protein_coding"`.
        pub feature_biotype: String,
        /// Ranked exon number, e.g., `"1/4"`.
        pub exon: Option<String>,
        /// Ranked intron number, e.g., `"1/4"`.
        pub intron: Option<String>,
        /// cDNA position, e.g., `"ENST00000302118.5:c.89C>G"`.
        pub hgvsc: Option<String>,
        /// Protein position, e.g., `"ENSP00000302118.5:p.Thr30Arg"`.
        pub hgvsp: Option<String>,
        /// cDNA position, e.g., `"89/1863"`.
        pub cdna_position: Option<String>,
        /// CDS position, e.g., `"89/1863"`.
        pub cds_position: Option<String>,
        /// Protein position, e.g., `"30/620"`.
        pub protein_position: Option<String>,
        /// Amino acids, e.g., `"T/R"`.
        pub amino_acids: Option<String>,
        /// Codons, e.g., `"gCg/gGg"`.
        pub codons: Option<String>,
        /// Existing variation info.
        pub existing_variation: Option<String>,
        /// dbSNP ID, e.g., `"rs28942080"`.
        pub dbsnp_id: Option<String>,
        /// Distance output of VEP.
        pub distance: Option<String>,
        /// Strand, e.g., `"1"`.
        pub strand: Option<String>,
        /// Flags, e.g., `"cds_end_NF"`.
        pub flags: Option<String>,
        /// Variant class, e.g., `"SNV"`.
        pub variant_class: Option<String>,
        /// Minimised output of VEP.
        pub minimised: Option<String>,
        /// Symbol source, e.g., `"HGNC"`.
        pub symbol_source: Option<String>,
        /// HGNC ID, e.g., `"HGNC:8706"`.
        pub hgnc_id: Option<String>,
        /// Whether this is the canonical transcript.
        pub canonical: bool,
        /// Transcript support level, e.g., `"1"`.
        pub tsl: Option<i32>,
        /// APPRIS annotation, e.g. `"P1"`.
        pub appris: Option<String>,
        /// CCDS ID, e.g., `"CCDS30547.1"`.
        pub ccds: Option<String>,
        /// Ensembl protein ID, e.g., `"ENSP00000302118"`.
        pub ensp: Option<String>,
        /// SwissProt ID, e.g., `"P04114"`.
        pub swissprot: Option<String>,
        /// TREMBL ID, e.g., `"Q5T4W7"`.
        pub trembl: Option<String>,
        /// UniParc ID, e.g., `"UPI000002D4B2"`.
        pub uniparc: Option<String>,
        /// Gene phenotype from VEP.
        pub gene_pheno: Option<String>,
        /// SIFT prediction, e.g., `"tolerated(0.06)"`.
        pub sift: Option<VepCommonPrediction>,
        /// PolyPhen prediction, e.g., `"benign(0.001)"`.
        pub polyphen: Option<VepCommonPrediction>,
        /// Protein domains, e.g., `\[["2p4e", "ENSP_mappings"\], \["2qtw", "ENSP_mappings"]\]`.
        pub domains: Vec<VepCommonDomain>,
        /// HGVS offset.
        pub hgvs_offset: Option<String>,
        /// Overall minor allele frequency.
        pub gmaf: Option<f32>,
        /// Minor allele frequency in AFR population.
        pub afr_maf: Option<f32>,
        /// Minor allele frequency in AMR population.
        pub amr_maf: Option<f32>,
        /// Minor allele frequency in EAS population.
        pub eas_maf: Option<f32>,
        /// Minor allele frequency in EUR population.
        pub eur_maf: Option<f32>,
        /// Minor allele frequency in SAS population.
        pub sas_maf: Option<f32>,
        /// Minor allele frequency in AA population.
        pub aa_maf: Option<f32>,
        /// Minor allele frequency in EA population.
        pub ea_maf: Option<f32>,
        /// Minor allele frequency in ExAC.
        pub exac_maf: Option<f32>,
        /// Minor allele frequency EXAC ADJ population.
        pub exac_adj_maf: Option<f32>,
        /// Minor allele frequency in ExAC AFR population.
        pub exac_afr_maf: Option<f32>,
        /// Minor allele frequency in ExAC AMR population.
        pub exac_amr_maf: Option<f32>,
        /// Minor allele frequency in ExAC EAS population.
        pub exac_eas_maf: Option<f32>,
        /// Minor allele frequency in ExAC FIN population.
        pub exac_fin_maf: Option<f32>,
        /// Minor allele frequency in ExAC NFE population.
        pub exac_nfe_maf: Option<f32>,
        /// Minor allele frequency in ExAC OTH population.
        pub exac_oth_maf: Option<f32>,
        /// Minor allele frequency in ExAC SAS population.
        pub exac_sas_maf: Option<f32>,
        /// Clinical significance.
        pub clin_sig: Option<String>,
        /// Whether the variant is somatic.
        pub somatic: Option<String>,
        /// Phenotype.
        pub pheno: Option<String>,
        /// Pubmed ID.
        pub pubmed: Option<String>,
        /// Motif name.
        pub motif_name: Option<String>,
        /// Motif pos.
        pub motif_pos: Option<String>,
        /// "high inf pos" from VEP.
        pub high_inf_pos: Option<String>,
        /// Motif score change.
        pub motif_score_change: Option<String>,
        /// Loss of function prediction.
        pub lof: Option<String>,
        /// Loss of function filter.
        pub lof_filter: Option<String>,
        /// Loss of function flags.
        pub lof_flags: Option<String>,
        /// Loss of function info.
        pub lof_info: Option<String>,
    }

    impl From<pbs::gnomad::vep_gnomad2::Vep> for Gnomad2Vep {
        fn from(value: pbs::gnomad::vep_gnomad2::Vep) -> Self {
            Gnomad2Vep {
                allele: value.allele,
                consequence: value.consequence,
                impact: value.impact,
                symbol: value.symbol,
                gene: value.gene,
                feature_type: value.feature_type,
                feature: value.feature,
                feature_biotype: value.feature_biotype,
                exon: value.exon,
                intron: value.intron,
                hgvsc: value.hgvsc,
                hgvsp: value.hgvsp,
                cdna_position: value.cdna_position,
                cds_position: value.cds_position,
                protein_position: value.protein_position,
                amino_acids: value.amino_acids,
                codons: value.codons,
                existing_variation: value.existing_variation,
                dbsnp_id: value.dbsnp_id,
                distance: value.distance,
                strand: value.strand,
                flags: value.flags,
                variant_class: value.variant_class,
                minimised: value.minimised,
                symbol_source: value.symbol_source,
                hgnc_id: value.hgnc_id,
                canonical: value.canonical,
                tsl: value.tsl,
                appris: value.appris,
                ccds: value.ccds,
                ensp: value.ensp,
                swissprot: value.swissprot,
                trembl: value.trembl,
                uniparc: value.uniparc,
                gene_pheno: value.gene_pheno,
                sift: value.sift.map(Into::into),
                polyphen: value.polyphen.map(Into::into),
                domains: value.domains.into_iter().map(Into::into).collect(),
                hgvs_offset: value.hgvs_offset,
                gmaf: value.gmaf,
                afr_maf: value.afr_maf,
                amr_maf: value.amr_maf,
                eas_maf: value.eas_maf,
                eur_maf: value.eur_maf,
                sas_maf: value.sas_maf,
                aa_maf: value.aa_maf,
                ea_maf: value.ea_maf,
                exac_maf: value.exac_maf,
                exac_adj_maf: value.exac_adj_maf,
                exac_afr_maf: value.exac_afr_maf,
                exac_amr_maf: value.exac_amr_maf,
                exac_eas_maf: value.exac_eas_maf,
                exac_fin_maf: value.exac_fin_maf,
                exac_nfe_maf: value.exac_nfe_maf,
                exac_oth_maf: value.exac_oth_maf,
                exac_sas_maf: value.exac_sas_maf,
                clin_sig: value.clin_sig,
                somatic: value.somatic,
                pheno: value.pheno,
                pubmed: value.pubmed,
                motif_name: value.motif_name,
                motif_pos: value.motif_pos,
                high_inf_pos: value.high_inf_pos,
                motif_score_change: value.motif_score_change,
                lof: value.lof,
                lof_filter: value.lof_filter,
                lof_flags: value.lof_flags,
                lof_info: value.lof_info,
            }
        }
    }

    /// Store the relevant allele counts and frequencies in a given sub cohort.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad2AlleleCounts {
        /// Number of alternate alleles in sub cohort.
        pub ac: i32,
        /// Total number of alleles in the sub cohort.
        pub an: i32,
        /// Number of homozygous alternate alleles in the sub cohort.
        pub nhomalt: i32,
        /// Alternate allele frequency in the sub cohort.
        pub af: f32,
    }

    impl From<pbs::gnomad::gnomad2::AlleleCounts> for Gnomad2AlleleCounts {
        fn from(value: pbs::gnomad::gnomad2::AlleleCounts) -> Self {
            Gnomad2AlleleCounts {
                ac: value.ac,
                an: value.an,
                nhomalt: value.nhomalt,
                af: value.af,
            }
        }
    }

    /// Store the allele counts for the given sub cohort and sub cohort factored by sex.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad2AlleleCountsBySex {
        /// Overall allele counts in the sub cohort.
        pub overall: Option<Gnomad2AlleleCounts>,
        /// Allele counts in female/XX karyotype individuals of sub cohort.
        pub xx: Option<Gnomad2AlleleCounts>,
        /// Allele counts in male/XY karyotype individuals of sub cohort.
        pub xy: Option<Gnomad2AlleleCounts>,
    }

    impl From<pbs::gnomad::gnomad2::AlleleCountsBySex> for Gnomad2AlleleCountsBySex {
        fn from(value: pbs::gnomad::gnomad2::AlleleCountsBySex) -> Self {
            Gnomad2AlleleCountsBySex {
                overall: value.overall.map(Into::into),
                xx: value.xx.map(Into::into),
                xy: value.xy.map(Into::into),
            }
        }
    }

    /// Store the allele counts for the given population.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad2PopulationAlleleCounts {
        /// Name of the population.
        pub population: String,
        /// The overall allele counts and the one by sex.
        pub counts: Option<Gnomad2AlleleCountsBySex>,
        /// The filtering allele frequency (using Poisson 95% CI).
        pub faf95: Option<f32>,
        /// The filtering allele frequency (using Poisson 99% CI).
        pub faf99: Option<f32>,
    }

    impl From<pbs::gnomad::gnomad2::PopulationAlleleCounts> for Gnomad2PopulationAlleleCounts {
        fn from(value: pbs::gnomad::gnomad2::PopulationAlleleCounts) -> Self {
            Gnomad2PopulationAlleleCounts {
                population: value.population,
                counts: value.counts.map(Into::into),
                faf95: value.faf95,
                faf99: value.faf99,
            }
        }
    }

    /// Store the allele counts for the given cohort.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad2CohortAlleleCounts {
        /// Name of the cohort.
        pub cohort: Option<String>,
        /// Allele counts for each population.
        pub by_population: Vec<Gnomad2PopulationAlleleCounts>,
        /// Allele counts by sex.
        pub by_sex: Option<Gnomad2AlleleCountsBySex>,
        /// Raw allele counts.
        pub raw: Option<Gnomad2AlleleCounts>,
        /// The population with maximum AF.
        pub popmax: Option<String>,
        /// Maximum allele frequency across populations (excluding samples of Ashkenazi, Finnish, and
        /// indeterminate ancestry).
        pub af_popmax: Option<f32>,
        /// Allele count in population with maximum AF.
        pub ac_popmax: Option<i32>,
        /// Total number of alleles in population with maximum AF.
        pub an_popmax: Option<i32>,
        /// Total number of homozygous individuals in population with maximum AF.
        pub nhomalt_popmax: Option<i32>,
    }

    impl From<pbs::gnomad::gnomad2::CohortAlleleCounts> for Gnomad2CohortAlleleCounts {
        fn from(value: pbs::gnomad::gnomad2::CohortAlleleCounts) -> Self {
            Gnomad2CohortAlleleCounts {
                cohort: value.cohort,
                by_population: value.by_population.into_iter().map(Into::into).collect(),
                by_sex: value.by_sex.map(Into::into),
                raw: value.raw.map(Into::into),
                popmax: value.popmax,
                af_popmax: value.af_popmax,
                ac_popmax: value.ac_popmax,
                an_popmax: value.an_popmax,
                nhomalt_popmax: value.nhomalt_popmax,
            }
        }
    }

    /// Encapsulate VCF INFO fields related to age.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad2AgeInfo {
        /// Histogram of ages of individuals with a homoplasmic variant; bin edges are: [30.0, 35.0,
        /// 40.0, 45.0, 50.0, 55.0, 60.0, 65.0, 70.0, 75.0, 80.0].
        pub age_hist_hom_bin_freq: Vec<i32>,
        /// Count of age values falling below lowest histogram bin edge for individuals with a
        /// homoplasmic variant.
        pub age_hist_hom_n_smaller: Option<i32>,
        /// Count of age values falling above highest histogram bin edge for individuals with a
        /// homoplasmic variant.
        pub age_hist_hom_n_larger: Option<i32>,
        /// Histogram of ages of individuals with a heteroplasmic variant; bin edges are: [30.0, 35.0,
        /// 40.0, 45.0, 50.0, 55.0, 60.0, 65.0, 70.0, 75.0, 80.0]
        pub age_hist_het_bin_freq: Vec<i32>,
        /// Count of age values falling below lowest histogram bin edge for individuals with a
        /// heteroplasmic variant.
        pub age_hist_het_n_smaller: Option<i32>,
        /// Count of age values falling above highest histogram bin edge for individuals with a
        /// heteroplasmic variant.
        pub age_hist_het_n_larger: Option<i32>,
    }

    impl From<pbs::gnomad::gnomad2::AgeInfo> for Gnomad2AgeInfo {
        fn from(value: pbs::gnomad::gnomad2::AgeInfo) -> Self {
            Gnomad2AgeInfo {
                age_hist_hom_bin_freq: value.age_hist_hom_bin_freq,
                age_hist_hom_n_smaller: value.age_hist_hom_n_smaller,
                age_hist_hom_n_larger: value.age_hist_hom_n_larger,
                age_hist_het_bin_freq: value.age_hist_het_bin_freq,
                age_hist_het_n_smaller: value.age_hist_het_n_smaller,
                age_hist_het_n_larger: value.age_hist_het_n_larger,
            }
        }
    }

    /// Encapsulate VCF INFO fields related to depth.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad2DepthInfo {
        /// Count of dp values falling above highest histogram bin edge for all individuals.
        pub dp_hist_all_n_larger: Option<i32>,
        /// Count of dp values falling above highest histogram bin edge for individuals with the
        /// alternative allele
        pub dp_hist_alt_n_larger: Option<i32>,
        /// Histogram of dp values for all individuals; bin edges are: [0.0, 200.0, 400.0, 600.0, 800.0,
        /// 1000.0, 1200.0, 1400.0, 1600.0, 1800.0, 2000.0]
        pub dp_hist_all_bin_freq: Vec<i32>,
        /// Histogram of dp values for individuals with the alternative allele; bin edges are: [0.0,
        /// 200.0, 400.0, 600.0, 800.0, 1000.0, 1200.0, 1400.0, 1600.0, 1800.0, 2000.0]
        pub dp_hist_alt_bin_freq: Vec<i32>,
    }

    impl From<pbs::gnomad::gnomad2::DepthInfo> for Gnomad2DepthInfo {
        fn from(value: pbs::gnomad::gnomad2::DepthInfo) -> Self {
            Gnomad2DepthInfo {
                dp_hist_all_n_larger: value.dp_hist_all_n_larger,
                dp_hist_alt_n_larger: value.dp_hist_alt_n_larger,
                dp_hist_all_bin_freq: value.dp_hist_all_bin_freq,
                dp_hist_alt_bin_freq: value.dp_hist_alt_bin_freq,
            }
        }
    }

    /// Encapsulate quality-related information.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad2QualityInfo {
        /// Phred-scaled p-value of Fisher's exact test for strand bias.
        pub fs: Option<f32>,
        /// Inbreeding coefficient as estimated from the genotype likelihoods per-sample when compared
        /// against the Hardy-Weinberg expectation.
        pub inbreeding_coeff: Option<f32>,
        /// Root mean square of the mapping quality of reads across all samples.
        pub mq: Option<f32>,
        /// Z-score from Wilcoxon rank sum test of alternate vs. reference read mapping qualities.
        pub mq_rank_sum: Option<f32>,
        /// Variant call confidence normalized by depth of sample reads supporting a variant.
        pub qd: Option<f32>,
        /// Z-score from Wilcoxon rank sum test of alternate vs. reference read position bias.
        pub read_pos_rank_sum: Option<f32>,
        /// Variant was used to build the positive training set of high-quality variants for VQSR.
        pub vqsr_positive_train_site: bool,
        /// Variant was used to build the negative training set of low-quality variants for VQSR.
        pub vqsr_negative_train_site: bool,
        /// Z-score from Wilcoxon rank sum test of alternate vs. reference base qualities.
        pub base_q_rank_sum: Option<f32>,
        /// Z-score from Wilcoxon rank sum test of alternate vs. reference number of hard clipped bases.
        pub clipping_rank_sum: Option<f32>,
        /// Strand bias estimated by the symmetric odds ratio test
        pub sor: Option<f32>,
        /// Depth of informative coverage for each sample; reads with MQ=255 or with bad mates are
        /// filtered.
        pub dp: Option<i32>,
        /// Log-odds ratio of being a true variant versus being a false positive under the trained VQSR
        /// Gaussian mixture model.
        pub vqslod: Option<f32>,
        /// Allele-specific worst-performing annotation in the VQSR Gaussian mixture model
        pub vqsr_culprit: Option<String>,
        /// Variant falls within a segmental duplication region
        pub segdup: bool,
        /// Variant falls within a low complexity region.
        pub lcr: bool,
        /// Variant falls within a reference decoy region.
        pub decoy: bool,
        /// Variant was a callset-wide doubleton that was transmitted within a family (i.e., a singleton
        /// amongst unrelated sampes in cohort).
        pub transmitted_singleton: bool,
        /// Maximum p-value over callset for binomial test of observed allele balance for a heterozygous
        /// genotype, given expectation of AB=0.5.
        pub pab_max: Option<f32>,
    }

    impl From<pbs::gnomad::gnomad2::QualityInfo> for Gnomad2QualityInfo {
        fn from(value: pbs::gnomad::gnomad2::QualityInfo) -> Self {
            Gnomad2QualityInfo {
                fs: value.fs,
                inbreeding_coeff: value.inbreeding_coeff,
                mq: value.mq,
                mq_rank_sum: value.mq_rank_sum,
                qd: value.qd,
                read_pos_rank_sum: value.read_pos_rank_sum,
                vqsr_positive_train_site: value.vqsr_positive_train_site,
                vqsr_negative_train_site: value.vqsr_negative_train_site,
                base_q_rank_sum: value.base_q_rank_sum,
                clipping_rank_sum: value.clipping_rank_sum,
                sor: value.sor,
                dp: value.dp,
                vqslod: value.vqslod,
                vqsr_culprit: value.vqsr_culprit,
                segdup: value.segdup,
                lcr: value.lcr,
                decoy: value.decoy,
                transmitted_singleton: value.transmitted_singleton,
                pab_max: value.pab_max,
            }
        }
    }

    /// Random forest related information.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad2RandomForestInfo {
        /// Random forest prediction probability for a site being a true variant.
        pub rf_tp_probability: f32,
        /// Variant was labelled as a positive example for training of random forest model.
        pub rf_positive_label: bool,
        /// Variant was labelled as a negative example for training of random forest model.
        pub rf_negative_label: bool,
        /// Random forest training label.
        pub rf_label: Option<String>,
        /// Variant was used in training random forest model.
        pub rf_train: bool,
    }

    impl From<pbs::gnomad::gnomad2::RandomForestInfo> for Gnomad2RandomForestInfo {
        fn from(value: pbs::gnomad::gnomad2::RandomForestInfo) -> Self {
            Gnomad2RandomForestInfo {
                rf_tp_probability: value.rf_tp_probability,
                rf_positive_label: value.rf_positive_label,
                rf_negative_label: value.rf_negative_label,
                rf_label: value.rf_label,
                rf_train: value.rf_train,
            }
        }
    }

    /// Liftover related information.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad2LiftoverInfo {
        /// The REF and the ALT alleles have been reverse complemented in liftover since the mapping from
        /// the previous reference to the current one was on the negative strand.
        pub reverse_complemented_alleles: bool,
        /// The REF and the ALT alleles have been swapped in liftover due to changes in the reference. It
        /// is possible that not all INFO annotations reflect this swap, and in the genotypes, only the
        /// GT, PL, and AD fields have been modified. You should check the TAGS_TO_REVERSE parameter that
        /// was used during the LiftOver to be sure.
        pub swapped_alleles: bool,
        /// A list of the original alleles (including REF) of the variant prior to liftover.  If the
        /// alleles were not changed during liftover, this attribute will be omitted.
        pub original_alleles: Vec<String>,
        /// The name of the source contig/chromosome prior to liftover.
        pub original_contig: Option<String>,
        /// The position of the variant on the source contig prior to liftover.
        pub original_start: Option<String>,
    }

    impl From<pbs::gnomad::gnomad2::LiftoverInfo> for Gnomad2LiftoverInfo {
        fn from(value: pbs::gnomad::gnomad2::LiftoverInfo) -> Self {
            Gnomad2LiftoverInfo {
                reverse_complemented_alleles: value.reverse_complemented_alleles,
                swapped_alleles: value.swapped_alleles,
                original_alleles: value.original_alleles,
                original_contig: value.original_contig,
                original_start: value.original_start,
            }
        }
    }

    /// Variant type related information.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad2VariantInfo {
        /// Variant type (snv, indel, multi-snv, multi-indel, or mixed).
        pub variant_type: String,
        /// Allele type (snv, ins, del, or mixed).
        pub allele_type: String,
        /// Total number of alternate alleles observed at variant locus.
        pub n_alt_alleles: i32,
        /// Variant type was mixed.
        pub was_mixed: bool,
        /// Variant locus coincides with a spanning deletion (represented by a star) observed elsewhere
        /// in the callset.
        pub has_star: bool,
    }

    impl From<pbs::gnomad::gnomad2::VariantInfo> for Gnomad2VariantInfo {
        fn from(value: pbs::gnomad::gnomad2::VariantInfo) -> Self {
            Gnomad2VariantInfo {
                variant_type: value.variant_type,
                allele_type: value.allele_type,
                n_alt_alleles: value.n_alt_alleles,
                was_mixed: value.was_mixed,
                has_star: value.has_star,
            }
        }
    }

    /// Protocol buffer for the gnomAD v2 VCF record.
    ///
    /// The more specialized fields from the INFO column are stored in separate, optional fields such
    /// that we don't end up with a humongous message.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad2Record {
        /// Chromosome name.
        pub chrom: String,
        /// 1-based start position.
        pub pos: i32,
        /// Reference allele.
        pub ref_allele: String,
        /// Alternate allele.
        pub alt_allele: String,
        /// Site-level filters.
        pub filters: Vec<Gnomad2Filter>,
        /// VEP annotation records.
        pub vep: Vec<Gnomad2Vep>,
        /// Variant allele counts in the different cohorts and population.
        ///
        /// The populations in gnomAD v2/3 are: empty for global, "controls", "non_cancer", "non_neuro",
        /// and "non_topmed".
        pub allele_counts: Vec<Gnomad2CohortAlleleCounts>,
        /// Variant (on sex chromosome) falls outside a pseudoautosomal region
        pub nonpar: bool,
        /// Information on lift-over from GRCh37 to GRCh38.
        pub liftover_info: Option<Gnomad2LiftoverInfo>,
        /// Random forest related information.
        pub rf_info: Option<Gnomad2RandomForestInfo>,
        /// Variant-related information details.
        pub variant_info: Option<Gnomad2VariantInfo>,
        /// Summary information for variant quality interpretation.
        pub quality_info: Option<Gnomad2QualityInfo>,
        /// Age-related information.
        pub age_info: Option<Gnomad2AgeInfo>,
        /// Depth of coverage-related information.
        pub depth_info: Option<Gnomad2DepthInfo>,
    }

    impl TryFrom<pbs::gnomad::gnomad2::Record> for Gnomad2Record {
        type Error = anyhow::Error;

        fn try_from(value: pbs::gnomad::gnomad2::Record) -> Result<Self, anyhow::Error> {
            Ok(Gnomad2Record {
                chrom: value.chrom,
                pos: value.pos,
                ref_allele: value.ref_allele,
                alt_allele: value.alt_allele,
                filters: value
                    .filters
                    .into_iter()
                    .map(|filter| {
                        Gnomad2Filter::try_from(pbs::gnomad::gnomad2::Filter::try_from(filter)?)
                    })
                    .collect::<Result<Vec<_>, _>>()?,
                vep: value.vep.into_iter().map(Into::into).collect(),
                allele_counts: value.allele_counts.into_iter().map(Into::into).collect(),
                nonpar: value.nonpar,
                liftover_info: value.liftover_info.map(Into::into),
                rf_info: value.rf_info.map(Into::into),
                variant_info: value.variant_info.map(Into::into),
                quality_info: value.quality_info.map(Into::into),
                age_info: value.age_info.map(Into::into),
                depth_info: value.depth_info.map(Into::into),
            })
        }
    }

    /// Protocol buffer enum for site-level filters.
    #[derive(
        Clone,
        Copy,
        Debug,
        PartialEq,
        Eq,
        Hash,
        PartialOrd,
        Ord,
        serde::Serialize,
        serde::Deserialize,
        strum::EnumString,
        utoipa::ToSchema,
    )]
    #[serde(rename_all = "snake_case")]
    #[strum(serialize_all = "snake_case")]
    pub enum Gnomad2Filter {
        /// Allele count is zero after filtering out low-confidence genotypes (GQ < 20; DP < 10; and AB <
        /// 0.2 for het calls).
        AlleleCountIsZero = 1,
        /// InbreedingCoeff < -0.3.
        InbreedingCoeff = 2,
        /// Passed all variant filters
        Pass = 3,
        /// Failed random forest filtering thresholds of 0.055272738028512555, 0.20641025579497013
        /// (probabilities of being a true positive variant) for SNPs, indels
        RandomForest = 4,
    }

    impl TryFrom<pbs::gnomad::gnomad2::Filter> for Gnomad2Filter {
        type Error = anyhow::Error;

        fn try_from(value: pbs::gnomad::gnomad2::Filter) -> Result<Self, Self::Error> {
            Ok(match value {
                pbs::gnomad::gnomad2::Filter::AlleleCountIsZero => Gnomad2Filter::AlleleCountIsZero,
                pbs::gnomad::gnomad2::Filter::InbreedingCoeff => Gnomad2Filter::InbreedingCoeff,
                pbs::gnomad::gnomad2::Filter::Pass => Gnomad2Filter::Pass,
                pbs::gnomad::gnomad2::Filter::RandomForest => Gnomad2Filter::RandomForest,
                _ => anyhow::bail!("Unknown Gnomad2Filter: {:?}", value),
            })
        }
    }

    /// Protocol buffer for the gnomAD-nuclear VEP predictions.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad3Vep {
        /// Allele of record.
        pub allele: String,
        /// Consequence, e.g., `"missense_variant"`.
        pub consequence: String,
        /// Impact, e.g., `"MODERATE"`.
        pub impact: String,
        /// Gene symbol, e.g., `"PCSK9"`.
        pub symbol: String,
        /// Gene ID, `e.g., "ENSG00000169174"`.
        pub gene: String,
        /// Feature type, e.g., `"Transcript"`.
        pub feature_type: String,
        /// Feature ID, e.g., `"ENST00000302118"`.
        pub feature: String,
        /// Feature biotype, e.g., `"protein_coding"`.
        pub feature_biotype: String,
        /// Ranked exon number, e.g., `"1/4"`.
        pub exon: Option<String>,
        /// Ranked intron number, e.g., `"1/4"`.
        pub intron: Option<String>,
        /// cDNA position, e.g., `"ENST00000302118.5:c.89C>G"`.
        pub hgvsc: Option<String>,
        /// Protein position, e.g., `"ENSP00000302118.5:p.Thr30Arg"`.
        pub hgvsp: Option<String>,
        /// cDNA position, e.g., `"89/1863"`.
        pub cdna_position: Option<String>,
        /// CDS position, e.g., `"89/1863"`.
        pub cds_position: Option<String>,
        /// Protein position, e.g., `"30/620"`.
        pub protein_position: Option<String>,
        /// Amino acids, e.g., `"T/R"`.
        pub amino_acids: Option<String>,
        /// Codons, e.g., `"gCg/gGg"`.
        pub codons: Option<String>,
        /// TODO: actually is optional int32 allele_num = 18;
        /// dbSNP ID, e.g., `"rs28942080"`.
        pub dbsnp_id: Option<String>,
        /// Distance output of VEP.
        pub distance: Option<String>,
        /// Strand, e.g., `"1"`.
        pub strand: Option<String>,
        /// Variant class, e.g., `"SNV"`.
        pub variant_class: Option<String>,
        /// Minimised output of VEP.
        pub minimised: Option<String>,
        /// Symbol source, e.g., `"HGNC"`.
        pub symbol_source: Option<String>,
        /// HGNC ID, e.g., `"HGNC:8706"`.
        pub hgnc_id: Option<String>,
        /// Whether this is the canonical transcript.
        pub canonical: Option<bool>,
        /// Transcript support level, e.g., `"1"`.
        pub tsl: Option<i32>,
        /// APPRIS annotation, e.g. `"P1"`.
        pub appris: Option<String>,
        /// CCDS ID, e.g., `"CCDS30547.1"`.
        pub ccds: Option<String>,
        /// Ensembl protein ID, e.g., `"ENSP00000302118"`.
        pub ensp: Option<String>,
        /// SwissProt ID, e.g., `"P04114"`.
        pub swissprot: Option<String>,
        /// TREMBL ID, e.g., `"Q5T4W7"`.
        pub trembl: Option<String>,
        /// UniParc ID, e.g., `"UPI000002D4B2"`.
        pub uniparc: Option<String>,
        /// Gene phenotype from VEP.
        pub gene_pheno: Option<String>,
        /// SIFT prediction, e.g., `"tolerated(0.06)"`.
        pub sift: Option<VepCommonPrediction>,
        /// PolyPhen prediction, e.g., `"benign(0.001)"`.
        pub polyphen: Option<VepCommonPrediction>,
        /// Protein domains, e.g., `\[["2p4e", "ENSP_mappings"\], \["2qtw", "ENSP_mappings"]\]`.
        pub domains: Vec<VepCommonDomain>,
        /// HGVS offset.
        pub hgvs_offset: Option<String>,
        /// Motif name.
        pub motif_name: Option<String>,
        /// Motif name.
        pub motif_pos: Option<String>,
        /// "high inf pos" from VEP.
        pub high_inf_pos: Option<String>,
        /// Motif score change.
        pub motif_score_change: Option<String>,
        /// Loss of function prediction.
        pub lof: Option<String>,
        /// Loss of function filter.
        pub lof_filter: Option<String>,
        /// Loss of function flags.
        pub lof_flags: Option<String>,
        /// Loss of function info.
        pub lof_info: Option<String>,
    }

    impl From<pbs::gnomad::vep_gnomad3::Vep> for Gnomad3Vep {
        fn from(value: pbs::gnomad::vep_gnomad3::Vep) -> Self {
            Gnomad3Vep {
                allele: value.allele,
                consequence: value.consequence,
                impact: value.impact,
                symbol: value.symbol,
                gene: value.gene,
                feature_type: value.feature_type,
                feature: value.feature,
                feature_biotype: value.feature_biotype,
                exon: value.exon,
                intron: value.intron,
                hgvsc: value.hgvsc,
                hgvsp: value.hgvsp,
                cdna_position: value.cdna_position,
                cds_position: value.cds_position,
                protein_position: value.protein_position,
                amino_acids: value.amino_acids,
                codons: value.codons,
                dbsnp_id: value.dbsnp_id,
                distance: value.distance,
                strand: value.strand,
                variant_class: value.variant_class,
                minimised: value.minimised,
                symbol_source: value.symbol_source,
                hgnc_id: value.hgnc_id,
                canonical: value.canonical,
                tsl: value.tsl,
                appris: value.appris,
                ccds: value.ccds,
                ensp: value.ensp,
                swissprot: value.swissprot,
                trembl: value.trembl,
                uniparc: value.uniparc,
                gene_pheno: value.gene_pheno,
                sift: value.sift.map(Into::into),
                polyphen: value.polyphen.map(Into::into),
                domains: value.domains.into_iter().map(Into::into).collect(),
                hgvs_offset: value.hgvs_offset,
                motif_name: value.motif_name,
                motif_pos: value.motif_pos,
                high_inf_pos: value.high_inf_pos,
                motif_score_change: value.motif_score_change,
                lof: value.lof,
                lof_filter: value.lof_filter,
                lof_flags: value.lof_flags,
                lof_info: value.lof_info,
            }
        }
    }

    /// Store details on variant effect predictions.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad3EffectInfo {
        /// PrimateAI's deleteriousness score from 0 (less deleterious) to 1 (more deleterious).
        pub primate_ai_score: Option<f32>,
        /// dbNSFP's Revel score from 0 to 1. Variants with higher scores are predicted to be
        /// more likely to be deleterious.
        pub revel_score: Option<f32>,
        /// Illumina's SpliceAI max delta score; interpreted as the probability of the variant
        /// being splice-altering.
        pub splice_ai_max_ds: Option<f32>,
        /// The consequence term associated with the max delta score in 'splice_ai_max_ds'.
        pub splice_ai_consequence: Option<String>,
        /// Raw CADD scores are interpretable as the extent to which the annotation profile for a given variant suggests that the variant is likely to be 'observed' (negative values) vs 'simulated' (positive values). Larger values are more deleterious.
        pub cadd_raw: Option<f32>,
        /// Cadd Phred-like scores ('scaled C-scores') ranging from 1 to 99, based on the rank of each variant relative to all possible 8.6 billion substitutions in the human reference genome. Larger values are more deleterious.
        pub cadd_phred: Option<f32>,
    }

    impl From<pbs::gnomad::gnomad3::EffectInfo> for Gnomad3EffectInfo {
        fn from(value: pbs::gnomad::gnomad3::EffectInfo) -> Self {
            Gnomad3EffectInfo {
                primate_ai_score: value.primate_ai_score,
                revel_score: value.revel_score,
                splice_ai_max_ds: value.splice_ai_max_ds,
                splice_ai_consequence: value.splice_ai_consequence,
                cadd_raw: value.cadd_raw,
                cadd_phred: value.cadd_phred,
            }
        }
    }

    /// Store the relevant allele counts and frequencies in a given sub cohort.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad3AlleleCounts {
        /// Number of alternate alleles in sub cohort.
        pub ac: i32,
        /// Total number of alleles in the sub cohort.
        pub an: i32,
        /// Number of homozygous alternate alleles in the sub cohort.
        pub nhomalt: i32,
        /// Alternate allele frequency in the sub cohort.
        pub af: f32,
    }

    impl From<pbs::gnomad::gnomad3::AlleleCounts> for Gnomad3AlleleCounts {
        fn from(value: pbs::gnomad::gnomad3::AlleleCounts) -> Self {
            Gnomad3AlleleCounts {
                ac: value.ac,
                an: value.an,
                nhomalt: value.nhomalt,
                af: value.af,
            }
        }
    }

    /// Store the allele counts for the given sub cohort and sub cohort factored by sex.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad3AlleleCountsBySex {
        /// Overall allele counts in the sub cohort.
        pub overall: Option<Gnomad3AlleleCounts>,
        /// Allele counts in female/XX karyotype individuals of sub cohort.
        pub xx: Option<Gnomad3AlleleCounts>,
        /// Allele counts in male/XY karyotype individuals of sub cohort.
        pub xy: Option<Gnomad3AlleleCounts>,
    }

    impl From<pbs::gnomad::gnomad3::AlleleCountsBySex> for Gnomad3AlleleCountsBySex {
        fn from(value: pbs::gnomad::gnomad3::AlleleCountsBySex) -> Self {
            Gnomad3AlleleCountsBySex {
                overall: value.overall.map(Into::into),
                xx: value.xx.map(Into::into),
                xy: value.xy.map(Into::into),
            }
        }
    }

    /// Store the allele counts for the given sub cohort in the given population.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad3PopulationAlleleCounts {
        /// Name of the population.
        pub population: String,
        /// The overall allele counts and the one by sex.
        pub counts: Option<Gnomad3AlleleCountsBySex>,
        /// The filtering allele frequency (using Poisson 95% CI).
        pub faf95: Option<f32>,
        /// The filtering allele frequency (using Poisson 99% CI).
        pub faf99: Option<f32>,
        /// The filtering allele frequency for XX samples (using Poisson 95% CI).
        pub faf95_xx: Option<f32>,
        /// The filtering allele frequency for XX samples (using Poisson 99% CI).
        pub faf99_xx: Option<f32>,
        /// The filtering allele frequency for XY samples (using Poisson 95% CI).
        pub faf95_xy: Option<f32>,
        /// The filtering allele frequency for XY samples (using Poisson 99% CI).
        pub faf99_xy: Option<f32>,
    }

    impl From<pbs::gnomad::gnomad3::PopulationAlleleCounts> for Gnomad3PopulationAlleleCounts {
        fn from(value: pbs::gnomad::gnomad3::PopulationAlleleCounts) -> Self {
            Gnomad3PopulationAlleleCounts {
                population: value.population,
                counts: value.counts.map(Into::into),
                faf95: value.faf95,
                faf99: value.faf99,
                faf95_xx: value.faf95_xx,
                faf99_xx: value.faf99_xx,
                faf95_xy: value.faf95_xy,
                faf99_xy: value.faf99_xy,
            }
        }
    }

    /// Store the allele counts for the given cohort.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad3CohortAlleleCounts {
        /// Name of the cohort.
        pub cohort: Option<String>,
        /// Allele counts for each population.
        pub by_population: Vec<Gnomad3PopulationAlleleCounts>,
        /// Allele counts by sex.
        pub by_sex: Option<Gnomad3AlleleCountsBySex>,
        /// Raw allele counts.
        pub raw: Option<Gnomad3AlleleCounts>,
        /// The population with maximum AF.
        pub popmax: Option<String>,
        /// Maximum allele frequency across populations (excluding samples of Ashkenazi, Finnish, and
        /// indeterminate ancestry).
        pub af_popmax: Option<f32>,
        /// Allele count in population with maximum AF.
        pub ac_popmax: Option<i32>,
        /// Total number of alleles in population with maximum AF.
        pub an_popmax: Option<i32>,
        /// Total number of homozygous individuals in population with maximum AF.
        pub nhomalt_popmax: Option<i32>,
    }

    impl From<pbs::gnomad::gnomad3::CohortAlleleCounts> for Gnomad3CohortAlleleCounts {
        fn from(value: pbs::gnomad::gnomad3::CohortAlleleCounts) -> Self {
            Gnomad3CohortAlleleCounts {
                cohort: value.cohort,
                by_population: value.by_population.into_iter().map(Into::into).collect(),
                by_sex: value.by_sex.map(Into::into),
                raw: value.raw.map(Into::into),
                popmax: value.popmax,
                af_popmax: value.af_popmax,
                ac_popmax: value.ac_popmax,
                an_popmax: value.an_popmax,
                nhomalt_popmax: value.nhomalt_popmax,
            }
        }
    }

    /// Encapsulate VCF INFO fields related to age.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad3AgeInfo {
        /// Histogram of ages of individuals with a homoplasmic variant; bin edges are: [30.0, 35.0,
        /// 40.0, 45.0, 50.0, 55.0, 60.0, 65.0, 70.0, 75.0, 80.0].
        pub age_hist_hom_bin_freq: Vec<i32>,
        /// Count of age values falling below lowest histogram bin edge for individuals with a
        /// homoplasmic variant.
        pub age_hist_hom_n_smaller: Option<i32>,
        /// Count of age values falling above highest histogram bin edge for individuals with a
        /// homoplasmic variant.
        pub age_hist_hom_n_larger: Option<i32>,
        /// Histogram of ages of individuals with a heteroplasmic variant; bin edges are: [30.0, 35.0,
        /// 40.0, 45.0, 50.0, 55.0, 60.0, 65.0, 70.0, 75.0, 80.0]
        pub age_hist_het_bin_freq: Vec<i32>,
        /// Count of age values falling below lowest histogram bin edge for individuals with a
        /// heteroplasmic variant.
        pub age_hist_het_n_smaller: Option<i32>,
        /// Count of age values falling above highest histogram bin edge for individuals with a
        /// heteroplasmic variant.
        pub age_hist_het_n_larger: Option<i32>,
    }

    impl From<pbs::gnomad::gnomad3::AgeInfo> for Gnomad3AgeInfo {
        fn from(value: pbs::gnomad::gnomad3::AgeInfo) -> Self {
            Gnomad3AgeInfo {
                age_hist_hom_bin_freq: value.age_hist_hom_bin_freq,
                age_hist_hom_n_smaller: value.age_hist_hom_n_smaller,
                age_hist_hom_n_larger: value.age_hist_hom_n_larger,
                age_hist_het_bin_freq: value.age_hist_het_bin_freq,
                age_hist_het_n_smaller: value.age_hist_het_n_smaller,
                age_hist_het_n_larger: value.age_hist_het_n_larger,
            }
        }
    }

    /// Encapsulate VCF INFO fields related to depth.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad3DepthInfo {
        /// Count of dp values falling above highest histogram bin edge for all individuals.
        pub dp_hist_all_n_larger: Option<i32>,
        /// Count of dp values falling above highest histogram bin edge for individuals with the
        /// alternative allele
        pub dp_hist_alt_n_larger: Option<i32>,
        /// Histogram of dp values for all individuals; bin edges are: [0.0, 200.0, 400.0, 600.0, 800.0,
        /// 1000.0, 1200.0, 1400.0, 1600.0, 1800.0, 2000.0]
        pub dp_hist_all_bin_freq: Vec<i32>,
        /// Histogram of dp values for individuals with the alternative allele; bin edges are: [0.0,
        /// 200.0, 400.0, 600.0, 800.0, 1000.0, 1200.0, 1400.0, 1600.0, 1800.0, 2000.0]
        pub dp_hist_alt_bin_freq: Vec<i32>,
    }

    impl From<pbs::gnomad::gnomad3::DepthInfo> for Gnomad3DepthInfo {
        fn from(value: pbs::gnomad::gnomad3::DepthInfo) -> Self {
            Gnomad3DepthInfo {
                dp_hist_all_n_larger: value.dp_hist_all_n_larger,
                dp_hist_alt_n_larger: value.dp_hist_alt_n_larger,
                dp_hist_all_bin_freq: value.dp_hist_all_bin_freq,
                dp_hist_alt_bin_freq: value.dp_hist_alt_bin_freq,
            }
        }
    }

    /// Encapsulate quality-related information.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad3QualityInfo {
        /// Allele-specific phred-scaled p-value of Fisher's exact test for strand bias.
        pub as_fs: Option<f32>,
        /// Inbreeding coefficient as estimated from the genotype likelihoods per-sample when compared
        /// against the Hardy-Weinberg expectation.
        pub inbreeding_coeff: Option<f32>,
        /// Allele-specific root mean square of the mapping quality of reads across all samples
        pub as_mq: Option<f32>,
        /// Z-score from Wilcoxon rank sum test of alternate vs. reference read mapping qualities.
        pub mq_rank_sum: Option<f32>,
        /// Allele-specific z-score from Wilcoxon rank sum test of alternate vs. reference read
        /// mapping qualities.
        pub as_mq_rank_sum: Option<f32>,
        /// Allele-specific variant call confidence normalized by depth of sample reads supporting a
        /// variant.
        pub as_qd: Option<f32>,
        /// Z-score from Wilcoxon rank sum test of alternate vs. reference read position bias.
        pub read_pos_rank_sum: Option<f32>,
        /// Allele-specific z-score from Wilcoxon rank sum test of alternate vs. reference read position bias.
        pub as_read_pos_rank_sum: Option<f32>,
        /// Allele-specific strand bias estimated by the symmetric odds ratio test.
        pub as_sor: Option<f32>,
        /// Variant was used to build the positive training set of high-quality variants for VQSR.
        pub positive_train_site: bool,
        /// Variant was used to build the negative training set of low-quality variants for VQSR.
        pub negative_train_site: bool,
        /// Allele-specific log-odds ratio of being a true variant versus being a false positive under the trained VQSR Gaussian mixture model.
        pub as_vqslod: Option<f32>,
        /// Allele-specific worst-performing annotation in the VQSR Gaussian mixture model.
        pub as_culprit: Option<String>,
        /// Variant falls within a segmental duplication region.
        pub segdup: bool,
        /// Variant falls within a low complexity region.
        pub lcr: bool,
        /// Variant was a callset-wide doubleton that was transmitted within a family (i.e., a singleton
        /// amongst unrelated sampes in cohort).
        pub transmitted_singleton: bool,
        /// Maximum p-value over callset for binomial test of observed allele balance for a heterozygous genotype, given expectation of 0.5.
        pub as_pab_max: Option<f32>,
        /// Allele-specific sum of PL\[0\] values; used to approximate the QUAL score.
        pub as_qual_approx: Option<i32>,
        /// Allele-specific forward/reverse read counts for strand bias tests.
        pub as_sb_table: Option<String>,
        /// Strand bias estimated by the symmetric odds ratio test (v4 only).
        pub sor: Option<f32>,
    }

    impl From<pbs::gnomad::gnomad3::QualityInfo> for Gnomad3QualityInfo {
        fn from(value: pbs::gnomad::gnomad3::QualityInfo) -> Self {
            Gnomad3QualityInfo {
                as_fs: value.as_fs,
                inbreeding_coeff: value.inbreeding_coeff,
                as_mq: value.as_mq,
                mq_rank_sum: value.mq_rank_sum,
                as_mq_rank_sum: value.as_mq_rank_sum,
                as_qd: value.as_qd,
                read_pos_rank_sum: value.read_pos_rank_sum,
                as_read_pos_rank_sum: value.as_read_pos_rank_sum,
                as_sor: value.as_sor,
                positive_train_site: value.positive_train_site,
                negative_train_site: value.negative_train_site,
                as_vqslod: value.as_vqslod,
                as_culprit: value.as_culprit,
                segdup: value.segdup,
                lcr: value.lcr,
                transmitted_singleton: value.transmitted_singleton,
                as_pab_max: value.as_pab_max,
                as_qual_approx: value.as_qual_approx,
                as_sb_table: value.as_sb_table,
                sor: value.sor,
            }
        }
    }

    /// Variant type related information.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad3VariantInfo {
        /// Variant type (snv, indel, multi-snv, multi-indel, or mixed).
        pub variant_type: String,
        /// Allele type (snv, ins, del, or mixed).
        pub allele_type: String,
        /// Total number of alternate alleles observed at variant locus.
        pub n_alt_alleles: i32,
        /// Variant type was mixed.
        pub was_mixed: bool,
        /// All samples are homozygous alternate for the variant.
        pub monoallelic: bool,
        /// Depth over variant genotypes (does not include depth of reference samples).
        pub var_dp: i32,
        /// Allele-specific depth over variant genotypes (does not include depth of reference samples) (v4 only).
        pub as_vardp: Option<i32>,
    }

    impl From<pbs::gnomad::gnomad3::VariantInfo> for Gnomad3VariantInfo {
        fn from(value: pbs::gnomad::gnomad3::VariantInfo) -> Self {
            Gnomad3VariantInfo {
                variant_type: value.variant_type,
                allele_type: value.allele_type,
                n_alt_alleles: value.n_alt_alleles,
                was_mixed: value.was_mixed,
                monoallelic: value.monoallelic,
                var_dp: value.var_dp,
                as_vardp: value.as_vardp,
            }
        }
    }

    /// Protocol buffer for the gnomAD-nuclear VCF record.
    ///
    /// The more specialized fields from the INFO column are stored in separate, optional fields such
    /// that we don't end up with a humongous message.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad3Record {
        /// Chromosome name.
        pub chrom: String,
        /// 1-based start position.
        pub pos: i32,
        /// Reference allele.
        pub ref_allele: String,
        /// Alternate allele.
        pub alt_allele: String,
        /// Site-level filters.
        pub filters: Vec<Gnomad3Filter>,
        /// VEP annotation records.
        pub vep: Vec<Gnomad3Vep>,
        /// Variant allele counts in the different cohorts and population.
        ///
        /// The populations in gnomAD v2/3 are: empty for global, "controls", "non_cancer", "non_neuro",
        /// and "non_topmed".
        pub allele_counts: Vec<Gnomad3CohortAlleleCounts>,
        /// Variant (on sex chromosome) falls outside a pseudoautosomal region
        pub nonpar: bool,
        /// Information on variant scores.
        pub effect_info: Option<Gnomad3EffectInfo>,
        /// Variant-related information details.
        pub variant_info: Option<Gnomad3VariantInfo>,
        /// Summary information for variant quality interpretation.
        pub quality_info: Option<Gnomad3QualityInfo>,
        /// Age-related information.
        pub age_info: Option<Gnomad3AgeInfo>,
        /// Depth of coverage-related information.
        pub depth_info: Option<Gnomad3DepthInfo>,
    }

    impl TryFrom<pbs::gnomad::gnomad3::Record> for Gnomad3Record {
        type Error = anyhow::Error;

        fn try_from(value: pbs::gnomad::gnomad3::Record) -> Result<Self, Self::Error> {
            Ok(Gnomad3Record {
                chrom: value.chrom,
                pos: value.pos,
                ref_allele: value.ref_allele,
                alt_allele: value.alt_allele,
                filters: value
                    .filters
                    .into_iter()
                    .map(|filter| {
                        Gnomad3Filter::try_from(pbs::gnomad::gnomad3::Filter::try_from(filter)?)
                    })
                    .collect::<Result<Vec<_>, _>>()?,
                vep: value.vep.into_iter().map(Into::into).collect(),
                allele_counts: value.allele_counts.into_iter().map(Into::into).collect(),
                nonpar: value.nonpar,
                effect_info: value.effect_info.map(Into::into),
                variant_info: value.variant_info.map(Into::into),
                quality_info: value.quality_info.map(Into::into),
                age_info: value.age_info.map(Into::into),
                depth_info: value.depth_info.map(Into::into),
            })
        }
    }

    /// Protocol buffer enum for site-level filters.
    #[derive(
        Clone,
        Copy,
        Debug,
        PartialEq,
        Eq,
        Hash,
        PartialOrd,
        Ord,
        serde::Serialize,
        serde::Deserialize,
        strum::EnumString,
        utoipa::ToSchema,
    )]
    #[serde(rename_all = "snake_case")]
    #[strum(serialize_all = "snake_case")]
    pub enum Gnomad3Filter {
        /// Allele count is zero after filtering out low-confidence genotypes (GQ < 20; DP < 10; and AB <
        /// 0.2 for het calls).
        AlleleCountIsZero = 1,
        /// Failed VQSR filtering thresholds of:
        ///
        /// gnomAD-genomes v3: -2.7739 for SNPs and -1.0606 for indels
        /// gnomAD-genomes v4: -2.502 for SNPs and -0.7156 for indels
        /// gnomAD-exomes v4: -1.4526 for SNPs and 0.0717 for indels
        AsVsqr = 2,
        /// InbreedingCoeff < -0.3.
        InbreedingCoeff = 3,
        /// Passed all variant filters
        Pass = 4,
    }

    impl TryFrom<pbs::gnomad::gnomad3::Filter> for Gnomad3Filter {
        type Error = anyhow::Error;

        fn try_from(value: pbs::gnomad::gnomad3::Filter) -> Result<Self, Self::Error> {
            Ok(match value {
                pbs::gnomad::gnomad3::Filter::AlleleCountIsZero => Gnomad3Filter::AlleleCountIsZero,
                pbs::gnomad::gnomad3::Filter::AsVsqr => Gnomad3Filter::AsVsqr,
                pbs::gnomad::gnomad3::Filter::InbreedingCoeff => Gnomad3Filter::InbreedingCoeff,
                pbs::gnomad::gnomad3::Filter::Pass => Gnomad3Filter::Pass,
                _ => anyhow::bail!("Unknown Filter: {:?}", value),
            })
        }
    }

    /// Protocol buffer for the gnomAD-nuclear VEP predictions.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad4Vep {
        /// Allele of record.
        pub allele: String,
        /// Consequence, e.g., `"missense_variant"`.
        pub consequence: String,
        /// Impact, e.g., `"MODERATE"`.
        pub impact: String,
        /// Gene symbol, e.g., `"PCSK9"`.
        pub symbol: String,
        /// Gene ID, `e.g., "ENSG00000169174"`.
        pub gene: String,
        /// Feature type, e.g., `"Transcript"`.
        pub feature_type: String,
        /// Feature ID, e.g., `"ENST00000302118"`.
        pub feature: String,
        /// Feature biotype, e.g., `"protein_coding"`.
        pub feature_biotype: String,
        /// Ranked exon number, e.g., `"1/4"`.
        pub exon: Option<String>,
        /// Ranked intron number, e.g., `"1/4"`.
        pub intron: Option<String>,
        /// cDNA position, e.g., `"ENST00000302118.5:c.89C>G"`.
        pub hgvsc: Option<String>,
        /// Protein position, e.g., `"ENSP00000302118.5:p.Thr30Arg"`.
        pub hgvsp: Option<String>,
        /// cDNA position, e.g., `"89/1863"`.
        pub cdna_position: Option<String>,
        /// CDS position, e.g., `"89/1863"`.
        pub cds_position: Option<String>,
        /// Protein position, e.g., `"30/620"`.
        pub protein_position: Option<String>,
        /// Amino acids, e.g., `"T/R"`.
        pub amino_acids: Option<String>,
        /// Codons, e.g., `"gCg/gGg"`.
        pub codons: Option<String>,
        /// Allele count.
        pub allele_num: Option<i32>,
        /// Distance output of VEP.
        pub distance: Option<String>,
        /// Strand, e.g., `"1"`.
        pub strand: Option<String>,
        /// Flags
        pub flags: Option<String>,
        /// Variant class, e.g., `"SNV"`.
        pub variant_class: Option<String>,
        /// Symbol source, e.g., `"HGNC"`.
        pub symbol_source: Option<String>,
        /// HGNC ID, e.g., `"HGNC:8706"`.
        pub hgnc_id: Option<String>,
        /// Whether this is the canonical transcript.
        pub canonical: Option<bool>,
        /// Presence in MANE Select
        pub mane_select: Option<bool>,
        /// Presence in MANE Plus Clinical
        pub mane_plus_clinical: Option<bool>,
        /// Transcript support level, e.g., `"1"`.
        pub tsl: Option<i32>,
        /// APPRIS annotation, e.g. `"P1"`.
        pub appris: Option<String>,
        /// CCDS ID, e.g., `"CCDS30547.1"`.
        pub ccds: Option<String>,
        /// Ensembl protein ID, e.g., `"ENSP00000302118"`.
        pub ensp: Option<String>,
        /// Uniprot isoform.
        pub uniprot_isoform: Option<String>,
        /// Value of VEP "SOURCE" field.
        pub source: Option<String>,
        /// Protein domains, e.g., `\[["2p4e", "ENSP_mappings"\], \["2qtw", "ENSP_mappings"]\]`.
        pub domains: Vec<VepCommonDomain>,
        /// miRNA information.
        pub mirna: Option<String>,
        /// HGVS offset.
        pub hgvs_offset: Option<String>,
        /// PubMed IDs
        pub pubmed: Option<String>,
        /// Motif name.
        pub motif_name: Option<String>,
        /// Motif name.
        pub motif_pos: Option<String>,
        /// "high inf pos" from VEP.
        pub high_inf_pos: Option<String>,
        /// Motif score change.
        pub motif_score_change: Option<String>,
        /// Transcription factors.
        pub transcription_factors: Option<String>,
        /// Loss of function prediction.
        pub lof: Option<String>,
        /// Loss of function filter.
        pub lof_filter: Option<String>,
        /// Loss of function flags.
        pub lof_flags: Option<String>,
        /// Loss of function info.
        pub lof_info: Option<String>,
    }

    impl From<pbs::gnomad::vep_gnomad4::Vep> for Gnomad4Vep {
        fn from(value: pbs::gnomad::vep_gnomad4::Vep) -> Self {
            Gnomad4Vep {
                allele: value.allele,
                consequence: value.consequence,
                impact: value.impact,
                symbol: value.symbol,
                gene: value.gene,
                feature_type: value.feature_type,
                feature: value.feature,
                feature_biotype: value.feature_biotype,
                exon: value.exon,
                intron: value.intron,
                hgvsc: value.hgvsc,
                hgvsp: value.hgvsp,
                cdna_position: value.cdna_position,
                cds_position: value.cds_position,
                protein_position: value.protein_position,
                amino_acids: value.amino_acids,
                codons: value.codons,
                allele_num: value.allele_num,
                distance: value.distance,
                strand: value.strand,
                flags: value.flags,
                variant_class: value.variant_class,
                symbol_source: value.symbol_source,
                hgnc_id: value.hgnc_id,
                canonical: value.canonical,
                mane_select: value.mane_select,
                mane_plus_clinical: value.mane_plus_clinical,
                tsl: value.tsl,
                appris: value.appris,
                ccds: value.ccds,
                ensp: value.ensp,
                uniprot_isoform: value.uniprot_isoform,
                source: value.source,
                domains: value.domains.into_iter().map(Into::into).collect(),
                mirna: value.mirna,
                hgvs_offset: value.hgvs_offset,
                pubmed: value.pubmed,
                motif_name: value.motif_name,
                motif_pos: value.motif_pos,
                high_inf_pos: value.high_inf_pos,
                motif_score_change: value.motif_score_change,
                transcription_factors: value.transcription_factors,
                lof: value.lof,
                lof_filter: value.lof_filter,
                lof_flags: value.lof_flags,
                lof_info: value.lof_info,
            }
        }
    }

    /// Store details on variant effect predictions.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad4EffectInfo {
        /// Pangolin's largest delta score across 2 splicing consequences, which reflects the probability of the variant being splice-altering">
        pub pangolin_largest_ds: Option<f32>,
        /// Base-wise conservation score across the 241 placental mammals in the Zoonomia project. Score ranges from -20 to 9.28, and reflects acceleration (faster evolution than expected under neutral drift, assigned negative scores) as well as conservation (slower than expected evolution, assigned positive scores).">
        pub phylop: Option<f32>,
        /// Score that predicts the possible impact of an amino acid substitution on the structure and function of a human protein, ranging from 0.0 (tolerated) to 1.0 (deleterious).  We prioritize max scores for MANE Select transcripts where possible and otherwise report a score for the canonical transcript.">
        pub polyphen_max: Option<f32>,
        /// The maximum REVEL score at a site's MANE Select or canonical transcript. It's an ensemble score for predicting the pathogenicity of missense variants (based on 13 other variant predictors). Scores ranges from 0 to 1. Variants with higher scores are predicted to be more likely to be deleterious.">
        pub revel_max: Option<f32>,
        /// Score reflecting the scaled probability of the amino acid substitution being tolerated, ranging from 0 to 1. Scores below 0.05 are predicted to impact protein function. We prioritize max scores for MANE Select transcripts where possible and otherwise report a score for the canonical transcript.">
        pub sift_max: Option<f32>,
        /// Illumina's SpliceAI max delta score; interpreted as the probability of the variant being splice-altering.">
        pub spliceai_ds_max: Option<f32>,
        /// Raw CADD scores are interpretable as the extent to which the annotation profile for a given variant suggests that the variant is likely to be 'observed' (negative values) vs 'simulated' (positive values). Larger values are more deleterious.
        pub cadd_raw: Option<f32>,
        /// Cadd Phred-like scores ('scaled C-scores') ranging from 1 to 99, based on the rank of each variant relative to all possible 8.6 billion substitutions in the human reference genome. Larger values are more deleterious.
        pub cadd_phred: Option<f32>,
    }

    impl From<pbs::gnomad::gnomad4::EffectInfo> for Gnomad4EffectInfo {
        fn from(value: pbs::gnomad::gnomad4::EffectInfo) -> Self {
            Gnomad4EffectInfo {
                pangolin_largest_ds: value.pangolin_largest_ds,
                phylop: value.phylop,
                polyphen_max: value.polyphen_max,
                revel_max: value.revel_max,
                sift_max: value.sift_max,
                spliceai_ds_max: value.spliceai_ds_max,
                cadd_raw: value.cadd_raw,
                cadd_phred: value.cadd_phred,
            }
        }
    }

    /// Store the allele counts for the given sub cohort in the given ancestry group.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad4AncestryGroupAlleleCounts {
        /// Name of the ancestry group.
        pub ancestry_group: String,
        /// The overall allele counts and the one by sex.
        pub counts: Option<Gnomad3AlleleCountsBySex>,
        /// The filtering allele frequency (using Poisson 95% CI).
        pub faf95: Option<f32>,
        /// The filtering allele frequency (using Poisson 99% CI).
        pub faf99: Option<f32>,
        /// The filtering allele frequency for XX samples (using Poisson 95% CI).
        pub faf95_xx: Option<f32>,
        /// The filtering allele frequency for XX samples (using Poisson 99% CI).
        pub faf99_xx: Option<f32>,
        /// The filtering allele frequency for XY samples (using Poisson 95% CI).
        pub faf95_xy: Option<f32>,
        /// The filtering allele frequency for XY samples (using Poisson 99% CI).
        pub faf99_xy: Option<f32>,
    }

    impl From<pbs::gnomad::gnomad4::AncestryGroupAlleleCounts> for Gnomad4AncestryGroupAlleleCounts {
        fn from(value: pbs::gnomad::gnomad4::AncestryGroupAlleleCounts) -> Self {
            Gnomad4AncestryGroupAlleleCounts {
                ancestry_group: value.ancestry_group,
                counts: value.counts.map(Into::into),
                faf95: value.faf95,
                faf99: value.faf99,
                faf95_xx: value.faf95_xx,
                faf99_xx: value.faf99_xx,
                faf95_xy: value.faf95_xy,
                faf99_xy: value.faf99_xy,
            }
        }
    }

    /// Store the allele counts for the given cohort.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad4CohortAlleleCounts {
        /// Name of the cohort.
        pub cohort: Option<String>,
        /// Allele counts for each population.
        pub by_ancestry_group: Vec<Gnomad4AncestryGroupAlleleCounts>,
        /// Allele counts by sex.
        pub by_sex: Option<Gnomad3AlleleCountsBySex>,
        /// Raw allele counts.
        pub raw: Option<Gnomad3AlleleCounts>,
        /// The ancestry group with maximum AF.
        pub grpmax: Option<String>,
        /// Maximum allele frequency across ancestry groups.
        pub af_grpmax: Option<f32>,
        /// Allele count in ancestry group with maximum AF.
        pub ac_grpmax: Option<i32>,
        /// Total number of alleles in ancestry group with maximum AF.
        pub an_grpmax: Option<i32>,
        /// Total number of homozygous individuals in ancestry group with maximum AF.
        pub nhomalt_grpmax: Option<i32>,
    }

    impl From<pbs::gnomad::gnomad4::CohortAlleleCounts> for Gnomad4CohortAlleleCounts {
        fn from(value: pbs::gnomad::gnomad4::CohortAlleleCounts) -> Self {
            Gnomad4CohortAlleleCounts {
                cohort: value.cohort,
                by_ancestry_group: value
                    .by_ancestry_group
                    .into_iter()
                    .map(Into::into)
                    .collect(),
                by_sex: value.by_sex.map(Into::into),
                raw: value.raw.map(Into::into),
                grpmax: value.grpmax,
                af_grpmax: value.af_grpmax,
                ac_grpmax: value.ac_grpmax,
                an_grpmax: value.an_grpmax,
                nhomalt_grpmax: value.nhomalt_grpmax,
            }
        }
    }

    /// VRS information
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad4VrsInfo {
        /// The computed identifiers for the GA4GH VRS Alleles corresponding to the values in the REF and ALT fields
        pub allele_ids: Vec<String>,
        /// Interresidue coordinates used as the location ends for the GA4GH VRS Alleles corresponding to the values in the REF and ALT fields
        pub ends: Vec<i32>,
        /// Interresidue coordinates used as the location starts for the GA4GH VRS Alleles corresponding to the values in the REF and ALT fields
        pub starts: Vec<i32>,
        /// The literal sequence states used for the GA4GH VRS Alleles corresponding to the values in the REF and ALT fields
        pub states: Vec<String>,
    }

    impl From<pbs::gnomad::gnomad4::VrsInfo> for Gnomad4VrsInfo {
        fn from(value: pbs::gnomad::gnomad4::VrsInfo) -> Self {
            Gnomad4VrsInfo {
                allele_ids: value.allele_ids,
                ends: value.ends,
                starts: value.starts,
                states: value.states,
            }
        }
    }

    /// Protocol buffer for the gnomAD-nuclear VCF record.
    ///
    /// The more specialized fields from the INFO column are stored in separate, optional fields such
    /// that we don't end up with a humongous message.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct Gnomad4Record {
        /// Chromosome name.
        pub chrom: String,
        /// 1-based start position.
        pub pos: i32,
        /// Reference allele.
        pub ref_allele: String,
        /// Alternate allele.
        pub alt_allele: String,
        /// Site-level filters.
        pub filters: Vec<Gnomad3Filter>,
        /// VEP annotation records.
        pub vep: Vec<Gnomad4Vep>,
        /// Variant allele counts in the different cohorts and population.
        ///
        /// The populations in gnomAD v4 are: empty for global, "joint" for exome+genomes.
        pub allele_counts: Vec<Gnomad4CohortAlleleCounts>,
        /// Variant (on sex chromosome) falls outside a pseudoautosomal region
        pub nonpar: bool,
        /// All samples are heterozygous for the variant
        pub only_het: bool,
        /// Variant falls outside of Broad exome capture regions (exomes only).
        pub outside_broad_capture_region: bool,
        /// Variant falls outside of UK Biobank exome capture regions(exomes only).
        pub outside_ukb_capture_region: bool,
        /// Variant was a callset-wide doubleton that was present only in two siblings (i.e., a singleton amongst unrelated samples in cohort) (exomes only).
        pub sibling_singleton: bool,
        /// Information on variant scores.
        pub effect_info: Option<Gnomad4EffectInfo>,
        /// Variant-related information details.
        pub variant_info: Option<Gnomad3VariantInfo>,
        /// Summary information for variant quality interpretation.
        pub quality_info: Option<Gnomad3QualityInfo>,
        /// Age-related information.
        pub age_info: Option<Gnomad3AgeInfo>,
        /// Depth of coverage-related information.
        pub depth_info: Option<Gnomad3DepthInfo>,
        /// VRS infos.
        pub vrs_info: Option<Gnomad4VrsInfo>,
    }

    impl TryFrom<pbs::gnomad::gnomad4::Record> for Gnomad4Record {
        type Error = anyhow::Error;

        fn try_from(value: pbs::gnomad::gnomad4::Record) -> Result<Self, Self::Error> {
            Ok(Gnomad4Record {
                chrom: value.chrom,
                pos: value.pos,
                ref_allele: value.ref_allele,
                alt_allele: value.alt_allele,
                filters: value
                    .filters
                    .into_iter()
                    .map(|filter| {
                        Gnomad3Filter::try_from(pbs::gnomad::gnomad3::Filter::try_from(filter)?)
                    })
                    .collect::<Result<Vec<_>, _>>()?,
                vep: value.vep.into_iter().map(Into::into).collect(),
                allele_counts: value.allele_counts.into_iter().map(Into::into).collect(),
                nonpar: value.nonpar,
                only_het: value.only_het,
                outside_broad_capture_region: value.outside_broad_capture_region,
                outside_ukb_capture_region: value.outside_ukb_capture_region,
                sibling_singleton: value.sibling_singleton,
                effect_info: value.effect_info.map(Into::into),
                variant_info: value.variant_info.map(Into::into),
                quality_info: value.quality_info.map(Into::into),
                age_info: value.age_info.map(Into::into),
                depth_info: value.depth_info.map(Into::into),
                vrs_info: value.vrs_info.map(Into::into),
            })
        }
    }

    /// Allow either a gnomAD v2/v3 or v4 record.
    #[derive(
        Clone, Debug, serde::Serialize, serde::Deserialize, strum::EnumString, utoipa::ToSchema,
    )]
    #[serde(rename_all = "snake_case")]
    #[strum(serialize_all = "snake_case")]
    pub enum GnomadRecord {
        /// gnomAD v2 record.
        Gnomad2(Gnomad2Record),
        /// gnomAD v3 record.
        Gnomad3(Gnomad3Record),
        /// gnomAD v4 record.
        Gnomad4(Gnomad4Record),
    }

    /// Encapsulate VCF INFO fields related to quality.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct GnomadMtdnaQualityInfo {
        /// Mean depth across all individuals for the site.
        pub dp_mean: Option<f32>,
        /// Mean MMQ (median mapping quality) across individuals with a variant for the site.
        pub mq_mean: Option<f32>,
        /// Mean TLOD (Log 10 likelihood ratio score of variant existing versus not existing) across
        /// individuals with a variant for the site.
        pub tlod_mean: Option<f32>,
    }

    impl From<pbs::gnomad::mtdna::QualityInfo> for GnomadMtdnaQualityInfo {
        fn from(value: pbs::gnomad::mtdna::QualityInfo) -> Self {
            GnomadMtdnaQualityInfo {
                dp_mean: value.dp_mean,
                mq_mean: value.mq_mean,
                tlod_mean: value.tlod_mean,
            }
        }
    }

    /// Encapsulate VCF INFO fields related to heteroplasmy levels.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct GnomadMtdnaHeteroplasmyInfo {
        /// Histogram of number of individuals with a heteroplasmy level below 0.1, bin edges are: [0.0,
        /// 0.1, 0.2, 0.30000000000000004, 0.4, 0.5, 0.6000000000000001, 0.7000000000000001, 0.8, 0.9,
        /// 1.0]
        pub heteroplasmy_below_min_het_threshold_hist: Vec<i32>,
        /// Histogram of heteroplasmy levels; bin edges are: [0.0, 0.1, 0.2, 0.30000000000000004, 0.4,
        /// 0.5, 0.6000000000000001, 0.7000000000000001, 0.8, 0.9, 1.0].
        pub hl_hist: Vec<i32>,
        /// Present if variant is found at an overall frequency of .001 across all samples with a
        /// heteroplasmy level > 0 and < 0.50 (includes variants <0.01 heteroplasmy which are
        /// subsequently filtered)
        pub common_low_heteroplasmy: bool,
        /// Maximum heteroplasmy level observed among all samples for that variant.
        pub max_hl: f32,
    }

    impl From<pbs::gnomad::mtdna::HeteroplasmyInfo> for GnomadMtdnaHeteroplasmyInfo {
        fn from(value: pbs::gnomad::mtdna::HeteroplasmyInfo) -> Self {
            GnomadMtdnaHeteroplasmyInfo {
                heteroplasmy_below_min_het_threshold_hist: value
                    .heteroplasmy_below_min_het_threshold_hist,
                hl_hist: value.hl_hist,
                common_low_heteroplasmy: value.common_low_heteroplasmy,
                max_hl: value.max_hl,
            }
        }
    }

    /// Encapsulate VCF INFO fields related to filter failure histograms.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct GnomadMtdnaFilterHistograms {
        /// Histogram of number of individuals failing the base_qual filter (alternate allele median base
        /// quality) across heteroplasmy levels, bin edges are: [0.0, 0.1, 0.2, 0.30000000000000004, 0.4,
        /// 0.5, 0.6000000000000001, 0.7000000000000001, 0.8, 0.9, 1.0]
        pub base_qual_hist: Vec<i32>,
        /// Histogram of number of individuals failing the position filter (median distance of alternate
        /// variants from end of reads) across heteroplasmy levels, bin edges are: [0.0, 0.1, 0.2, 0.
        /// 30000000000000004, 0.4, 0.5, 0.6000000000000001, 0.7000000000000001, 0.8, 0.9, 1.0]
        pub position_hist: Vec<i32>,
        /// Histogram of number of individuals failing the strand_bias filter (evidence for alternate
        /// allele comes from one read direction only) across heteroplasmy levels, bin edges are: [0.0,
        /// 0.1, 0.2, 0.30000000000000004, 0.4, 0.5, 0.6000000000000001, 0.7000000000000001, 0.8, 0.9,
        /// 1.0]
        pub strand_bias_hist: Vec<i32>,
        /// Histogram of number of individuals failing the weak_evidence filter (mutation does not meet
        /// likelihood threshold) across heteroplasmy levels, bin edges are: [0.0, 0.1, 0.2,
        /// 0.30000000000000004, 0.4, 0.5, 0.6000000000000001, 0.7000000000000001, 0.8, 0.9, 1.0]
        pub weak_evidence_hist: Vec<i32>,
        /// Histogram of number of individuals failing the contamination filter across heteroplasmy
        /// levels, bin edges are: [0.0, 0.1, 0.2, 0.30000000000000004, 0.4, 0.5, 0.6000000000000001,
        /// 0.7000000000000001, 0.8, 0.9, 1.0]
        pub contamination_hist: Vec<i32>,
    }

    impl From<pbs::gnomad::mtdna::FilterHistograms> for GnomadMtdnaFilterHistograms {
        fn from(value: pbs::gnomad::mtdna::FilterHistograms) -> Self {
            GnomadMtdnaFilterHistograms {
                base_qual_hist: value.base_qual_hist,
                position_hist: value.position_hist,
                strand_bias_hist: value.strand_bias_hist,
                weak_evidence_hist: value.weak_evidence_hist,
                contamination_hist: value.contamination_hist,
            }
        }
    }

    /// Encapsulate VCF INFO fields related to populations.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct GnomadMtdnaPopulationInfo {
        /// List of overall allele number for each population, population order: ['afr', 'ami', 'amr',
        /// 'asj', 'eas', 'fin', 'nfe', 'oth', 'sas', 'mid']
        pub pop_an: Vec<i32>,
        /// List of AC_het for each population, population order: ['afr', 'ami', 'amr', 'asj', 'eas',
        /// 'fin', 'nfe', 'oth', 'sas', 'mid']
        pub pop_ac_het: Vec<i32>,
        /// List of AC_hom for each population, population order: ['afr', 'ami', 'amr', 'asj', 'eas',
        /// 'fin', 'nfe', 'oth', 'sas', 'mid']
        pub pop_ac_hom: Vec<i32>,
        /// List of AF_hom for each population, population order: ['afr', 'ami', 'amr', 'asj', 'eas',
        /// 'fin', 'nfe', 'oth', 'sas', 'mid']
        pub pop_af_hom: Vec<f32>,
        /// List of AF_het for each population, population order: ['afr', 'ami', 'amr', 'asj', 'eas',
        /// 'fin', 'nfe', 'oth', 'sas', 'mid']
        pub pop_af_het: Vec<f32>,
        /// Histogram of heteroplasmy levels for each population; bin edges are: [0.0, 0.1, 0.2,
        /// 0.30000000000000004, 0.4, 0.5, 0.6000000000000001, 0.7000000000000001, 0.8, 0.9, 1.0],
        /// population order: \['afr', 'ami', 'amr', 'asj', 'eas', 'fin', 'nfe', 'oth', 'sas', 'mid'\]
        ///
        /// Note that we encode this by concatenating all lists here because of limitations in
        /// protocolbuffers (no native nested repeated fields).
        pub pop_hl_hist: Vec<i32>,
    }

    impl From<pbs::gnomad::mtdna::PopulationInfo> for GnomadMtdnaPopulationInfo {
        fn from(value: pbs::gnomad::mtdna::PopulationInfo) -> Self {
            GnomadMtdnaPopulationInfo {
                pop_an: value.pop_an,
                pop_ac_het: value.pop_ac_het,
                pop_ac_hom: value.pop_ac_hom,
                pop_af_hom: value.pop_af_hom,
                pop_af_het: value.pop_af_het,
                pop_hl_hist: value.pop_hl_hist,
            }
        }
    }
    /// Encapsulate VCF INFO fields related to haplogroups.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct GnomadMtdnaHaplogroupInfo {
        /// Present if variant is present as a haplogroup defining variant in PhyloTree build 17.
        pub hap_defining_variant: bool,
        /// List of overall allele number for each haplogroup, haplogroup order: ['A', 'B', 'C', 'D',
        /// 'E', 'F', 'G', 'H', 'HV', 'I', 'J', 'K', 'L0', 'L1', 'L2', 'L3', 'L4', 'L5', 'M', 'N', 'P',
        /// 'R', 'T', 'U', 'V', 'W', 'X', 'Y', 'Z']
        pub hap_an: Vec<i32>,
        /// List of AC_het for each haplogroup, haplogroup order: ['A', 'B', 'C', 'D', 'E', 'F', 'G',
        /// 'H', 'HV', 'I', 'J', 'K', 'L0', 'L1', 'L2', 'L3', 'L4', 'L5', 'M', 'N', 'P', 'R', 'T', 'U',
        /// 'V', 'W', 'X', 'Y', 'Z']
        pub hap_ac_het: Vec<i32>,
        /// List of AC_hom for each haplogroup, haplogroup order: ['A', 'B', 'C', 'D', 'E', 'F', 'G',
        /// 'H', 'HV', 'I', 'J', 'K', 'L0', 'L1', 'L2', 'L3', 'L4', 'L5', 'M', 'N', 'P', 'R', 'T', 'U',
        /// 'V', 'W', 'X', 'Y', 'Z']
        pub hap_ac_hom: Vec<i32>,
        /// List of AF_het for each haplogroup, haplogroup order: ['A', 'B', 'C', 'D', 'E', 'F', 'G',
        /// 'H', 'HV', 'I', 'J', 'K', 'L0', 'L1', 'L2', 'L3', 'L4', 'L5', 'M', 'N', 'P', 'R', 'T', 'U',
        /// 'V', 'W', 'X', 'Y', 'Z']
        pub hap_af_het: Vec<f32>,
        /// List of AF_hom for each haplogroup, haplogroup order: ['A', 'B', 'C', 'D', 'E', 'F', 'G',
        /// 'H', 'HV', 'I', 'J', 'K', 'L0', 'L1', 'L2', 'L3', 'L4', 'L5', 'M', 'N', 'P', 'R', 'T', 'U',
        /// 'V', 'W', 'X', 'Y', 'Z']
        pub hap_af_hom: Vec<f32>,
        /// Histogram of heteroplasmy levels for each haplogroup; bin edges are: [0.0, 0.1, 0.2,
        /// 0.30000000000000004, 0.4, 0.5, 0.6000000000000001, 0.7000000000000001, 0.8, 0.9, 1.0],
        /// haplogroup order: ['A', 'B', 'C', 'D', 'E', 'F', 'G', 'H', 'HV', 'I', 'J', 'K', 'L0', 'L1',
        /// 'L2', 'L3', 'L4', 'L5', 'M', 'N', 'P', 'R', 'T', 'U', 'V', 'W', 'X', 'Y', 'Z']
        ///
        /// Note that we encode this by concatenating all lists here because of limitations in
        /// protocolbuffers (no native nested repeated fields).
        pub hap_hl_hist: Vec<i32>,
        /// List of filtering allele frequency for each haplogroup restricted to homoplasmic variants,
        /// haplogroup order: ['A', 'B', 'C', 'D', 'E', 'F', 'G', 'H', 'HV', 'I', 'J', 'K', 'L0', 'L1',
        /// 'L2', 'L3', 'L4', 'L5', 'M', 'N', 'P', 'R', 'T', 'U', 'V', 'W', 'X', 'Y', 'Z']
        pub hap_faf_hom: Vec<f32>,
        /// Haplogroup with maximum AF_hom.
        pub hapmax_af_hom: Option<String>,
        /// Haplogroup with maximum AF_het.
        pub hapmax_af_het: Option<String>,
        /// Maximum filtering allele frequency across haplogroups restricted to homoplasmic variants.
        pub faf_hapmax_hom: Option<f32>,
    }

    impl From<pbs::gnomad::mtdna::HaplogroupInfo> for GnomadMtdnaHaplogroupInfo {
        fn from(value: pbs::gnomad::mtdna::HaplogroupInfo) -> Self {
            GnomadMtdnaHaplogroupInfo {
                hap_defining_variant: value.hap_defining_variant,
                hap_an: value.hap_an,
                hap_ac_het: value.hap_ac_het,
                hap_ac_hom: value.hap_ac_hom,
                hap_af_het: value.hap_af_het,
                hap_af_hom: value.hap_af_hom,
                hap_hl_hist: value.hap_hl_hist,
                hap_faf_hom: value.hap_faf_hom,
                hapmax_af_hom: value.hapmax_af_hom,
                hapmax_af_het: value.hapmax_af_het,
                faf_hapmax_hom: value.faf_hapmax_hom,
            }
        }
    }

    /// Encapsulate VCF INFO fields related to age.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct GnomadMtdnaAgeInfo {
        /// Histogram of ages of individuals with a homoplasmic variant; bin edges are: [30.0, 35.0,
        /// 40.0, 45.0, 50.0, 55.0, 60.0, 65.0, 70.0, 75.0, 80.0].
        pub age_hist_hom_bin_freq: Vec<i32>,
        /// Count of age values falling below lowest histogram bin edge for individuals with a
        /// homoplasmic variant.
        pub age_hist_hom_n_smaller: Option<i32>,
        /// Count of age values falling above highest histogram bin edge for individuals with a
        /// homoplasmic variant.
        pub age_hist_hom_n_larger: Option<i32>,
        /// Histogram of ages of individuals with a heteroplasmic variant; bin edges are: [30.0, 35.0,
        /// 40.0, 45.0, 50.0, 55.0, 60.0, 65.0, 70.0, 75.0, 80.0]
        pub age_hist_het_bin_freq: Vec<i32>,
        /// Count of age values falling below lowest histogram bin edge for individuals with a
        /// heteroplasmic variant.
        pub age_hist_het_n_smaller: Option<i32>,
        /// Count of age values falling above highest histogram bin edge for individuals with a
        /// heteroplasmic variant.
        pub age_hist_het_n_larger: Option<i32>,
    }

    impl From<pbs::gnomad::mtdna::AgeInfo> for GnomadMtdnaAgeInfo {
        fn from(value: pbs::gnomad::mtdna::AgeInfo) -> Self {
            GnomadMtdnaAgeInfo {
                age_hist_hom_bin_freq: value.age_hist_hom_bin_freq,
                age_hist_hom_n_smaller: value.age_hist_hom_n_smaller,
                age_hist_hom_n_larger: value.age_hist_hom_n_larger,
                age_hist_het_bin_freq: value.age_hist_het_bin_freq,
                age_hist_het_n_smaller: value.age_hist_het_n_smaller,
                age_hist_het_n_larger: value.age_hist_het_n_larger,
            }
        }
    }

    /// Encapsulate VCF INFO fields related to depth.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct GnomadMtdnaDepthInfo {
        /// Count of dp values falling above highest histogram bin edge for all individuals.
        pub dp_hist_all_n_larger: Option<i32>,
        /// Count of dp values falling above highest histogram bin edge for individuals with the
        /// alternative allele
        pub dp_hist_alt_n_larger: Option<i32>,
        /// Histogram of dp values for all individuals; bin edges are: [0.0, 200.0, 400.0, 600.0, 800.0,
        /// 1000.0, 1200.0, 1400.0, 1600.0, 1800.0, 2000.0]
        pub dp_hist_all_bin_freq: Vec<i32>,
        /// Histogram of dp values for individuals with the alternative allele; bin edges are: [0.0,
        /// 200.0, 400.0, 600.0, 800.0, 1000.0, 1200.0, 1400.0, 1600.0, 1800.0, 2000.0]
        pub dp_hist_alt_bin_freq: Vec<i32>,
    }

    impl From<pbs::gnomad::mtdna::DepthInfo> for GnomadMtdnaDepthInfo {
        fn from(value: pbs::gnomad::mtdna::DepthInfo) -> Self {
            GnomadMtdnaDepthInfo {
                dp_hist_all_n_larger: value.dp_hist_all_n_larger,
                dp_hist_alt_n_larger: value.dp_hist_alt_n_larger,
                dp_hist_all_bin_freq: value.dp_hist_all_bin_freq,
                dp_hist_alt_bin_freq: value.dp_hist_alt_bin_freq,
            }
        }
    }

    /// Protocol buffer for the gnomAD-mtDNA VCF record.
    ///
    /// The more specialized fields from the INFO column are stored in separate, optional fields such
    /// that we don't end up with a humongous message.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct GnomadMtdnaRecord {
        /// Chromosome name.
        pub chrom: String,
        /// 1-based start position.
        pub pos: i32,
        /// Reference allele.
        pub ref_allele: String,
        /// Alternate allele.
        pub alt_allele: String,
        /// Variant in format of RefPosAlt
        pub variant_collapsed: String,
        /// Excluded allele count (number of individuals in which the variant was filtered out).
        pub excluded_ac: i32,
        /// Overall allele number (number of samples with non-missing genotype).
        pub an: i32,
        /// Allele count restricted to variants with a heteroplasmy level >= 0.95.
        pub ac_hom: i32,
        /// Allele count restricted to variants with a heteroplasmy level >= 0.10 and < 0.95.
        pub ac_het: i32,
        /// Allele frequency restricted to variants with a heteroplasmy level >= 0.95.
        pub af_hom: f32,
        /// Allele frequency restricted to variants with a heteroplasmy level >= 0.10 and < 0.95.
        pub af_het: f32,
        /// Site-level filters.
        pub filters: Vec<GnomadMtdnaFilter>,
        /// MitoTip raw score
        pub mitotip_score: Option<f32>,
        /// MitoTip score interpretation
        pub mitotip_trna_prediction: Option<String>,
        /// tRNA pathogenicity classification from PON-mt-tRNA
        pub pon_mt_trna_prediction: Option<String>,
        /// tRNA ML_probability_of_pathogenicity from PON-mt-tRNA
        pub pon_ml_probability_of_pathogenicity: Option<String>,
        /// VEP v3 annotation records.
        pub vep: Vec<Gnomad3Vep>,
        /// Summary information for variant quality interpretation.
        pub quality_info: Option<GnomadMtdnaQualityInfo>,
        /// Information related to heteroplasmy levels.
        pub heteroplasmy_info: Option<GnomadMtdnaHeteroplasmyInfo>,
        /// Histograms related to variant quality filters.
        pub filter_histograms: Option<GnomadMtdnaFilterHistograms>,
        /// Population-related information.
        pub population_info: Option<GnomadMtdnaPopulationInfo>,
        /// Haplogroup-related information.
        pub haplogroup_info: Option<GnomadMtdnaHaplogroupInfo>,
        /// Age-related information.
        pub age_info: Option<GnomadMtdnaAgeInfo>,
        /// Depth of coverage-related information.
        pub depth_info: Option<GnomadMtdnaDepthInfo>,
    }

    impl TryFrom<pbs::gnomad::mtdna::Record> for GnomadMtdnaRecord {
        type Error = anyhow::Error;

        fn try_from(value: pbs::gnomad::mtdna::Record) -> Result<Self, Self::Error> {
            Ok(GnomadMtdnaRecord {
                chrom: value.chrom,
                pos: value.pos,
                ref_allele: value.ref_allele,
                alt_allele: value.alt_allele,
                variant_collapsed: value.variant_collapsed,
                excluded_ac: value.excluded_ac,
                an: value.an,
                ac_hom: value.ac_hom,
                ac_het: value.ac_het,
                af_hom: value.af_hom,
                af_het: value.af_het,
                filters: value
                    .filters
                    .into_iter()
                    .map(|filter| {
                        GnomadMtdnaFilter::try_from(
                            pbs::gnomad::mtdna::Filter::try_from(filter)
                                .map_err(anyhow::Error::from)?,
                        )
                    })
                    .collect::<Result<_, _>>()?,
                mitotip_score: value.mitotip_score,
                mitotip_trna_prediction: value.mitotip_trna_prediction,
                pon_mt_trna_prediction: value.pon_mt_trna_prediction,
                pon_ml_probability_of_pathogenicity: value.pon_ml_probability_of_pathogenicity,
                vep: value.vep.into_iter().map(Into::into).collect(),
                quality_info: value.quality_info.map(Into::into),
                heteroplasmy_info: value.heteroplasmy_info.map(Into::into),
                filter_histograms: value.filter_histograms.map(Into::into),
                population_info: value.population_info.map(Into::into),
                haplogroup_info: value.haplogroup_info.map(Into::into),
                age_info: value.age_info.map(Into::into),
                depth_info: value.depth_info.map(Into::into),
            })
        }
    }

    /// Protocol buffer enum for site-level filters.
    #[derive(
        Clone,
        Copy,
        Debug,
        PartialEq,
        Eq,
        Hash,
        PartialOrd,
        Ord,
        serde::Serialize,
        serde::Deserialize,
        strum::Display,
        strum::EnumString,
        utoipa::ToSchema,
    )]
    #[serde(rename_all = "snake_case")]
    #[strum(serialize_all = "snake_case")]
    pub enum GnomadMtdnaFilter {
        /// Variant overlaps site that is commonly reported in literature to be artifact prone.
        ArtifactProneSite,
        /// Allele where all samples with the variant call had at least 2 different heteroplasmic indels
        /// called at the position.
        IndelStack,
        /// No-pass-genotypes site (no individuals were PASS for the variant).
        NoPassGenotype,
    }

    impl TryFrom<pbs::gnomad::mtdna::Filter> for GnomadMtdnaFilter {
        type Error = anyhow::Error;

        fn try_from(value: pbs::gnomad::mtdna::Filter) -> Result<Self, Self::Error> {
            Ok(match value {
                pbs::gnomad::mtdna::Filter::ArtifactProneSite => {
                    GnomadMtdnaFilter::ArtifactProneSite
                }
                pbs::gnomad::mtdna::Filter::IndelStack => GnomadMtdnaFilter::IndelStack,
                pbs::gnomad::mtdna::Filter::NoPassGenotype => GnomadMtdnaFilter::NoPassGenotype,
                _ => anyhow::bail!("unknown gnomad::mtdna::Filter: {:?}", value),
            })
        }
    }

    /// A record corresponding to dbSNP VCF.
    #[derive(Debug, Default, Clone, serde::Serialize, serde::Deserialize, utoipa::ToSchema)]
    pub struct DbsnpRecord {
        /// Chromosome name.
        pub chrom: String,
        /// 1-based start position.
        pub pos: i32,
        /// Reference allele.
        pub ref_allele: String,
        /// Alternate allele.
        pub alt_allele: String,
        /// The rs ID.
        pub rs_id: i32,
    }

    impl From<crate::pbs::dbsnp::Record> for DbsnpRecord {
        fn from(value: crate::pbs::dbsnp::Record) -> Self {
            DbsnpRecord {
                chrom: value.chrom,
                pos: value.pos,
                ref_allele: value.ref_allele,
                alt_allele: value.alt_allele,
                rs_id: value.rs_id,
            }
        }
    }

    /// A HelixMtDb record.
    #[derive(Debug, Default, Clone, serde::Serialize, serde::Deserialize, utoipa::ToSchema)]
    pub struct HelixMtDbRecord {
        /// Chromosome name.
        pub chrom: String,
        /// 1-based start position.
        pub pos: i32,
        /// Reference allele.
        pub ref_allele: String,
        /// / Alternate allele.
        pub alt_allele: String,
        /// Total number of individuals.
        pub num_total: i32,
        /// Number of homoplasmic carriers.
        pub num_het: i32,
        /// Number of heteroplasmic carriers.
        pub num_hom: i32,
        /// Feature type.
        pub feature_type: String,
        /// Gene name.
        pub gene_name: String,
    }

    impl From<crate::pbs::helixmtdb::Record> for HelixMtDbRecord {
        fn from(val: crate::pbs::helixmtdb::Record) -> Self {
            HelixMtDbRecord {
                chrom: val.chrom,
                pos: val.pos,
                ref_allele: val.ref_allele,
                alt_allele: val.alt_allele,
                num_total: val.num_total,
                num_het: val.num_het,
                num_hom: val.num_hom,
                feature_type: val.feature_type,
                gene_name: val.gene_name,
            }
        }
    }

    /// A UCSC conservation record.
    #[derive(Debug, Default, Clone, serde::Serialize, serde::Deserialize, utoipa::ToSchema)]
    pub struct UcscConservationRecord {
        /// Chromosome name.
        pub chrom: String,
        /// 1-based, inclusive start position.
        pub start: i32,
        /// 1-based, inclusive stop position.
        pub stop: i32,
        /// HGNC identifier.
        pub hgnc_id: String,
        /// ENST identifier.
        pub enst_id: String,
        /// Exon number (1-based).
        pub exon_num: i32,
        /// Exon count.
        pub exon_count: i32,
        /// Alignment.
        pub alignment: String,
    }

    impl From<crate::pbs::cons::Record> for UcscConservationRecord {
        fn from(value: crate::pbs::cons::Record) -> Self {
            UcscConservationRecord {
                chrom: value.chrom,
                start: value.start,
                stop: value.stop,
                hgnc_id: value.hgnc_id,
                enst_id: value.enst_id,
                exon_num: value.exon_num,
                exon_count: value.exon_count,
                alignment: value.alignment,
            }
        }
    }

    /// List of `Record`s.
    #[derive(Debug, Default, Clone, serde::Serialize, serde::Deserialize, utoipa::ToSchema)]
    pub struct UcscConservationRecordList {
        /// The records in the list.
        pub records: Vec<UcscConservationRecord>,
    }

    impl From<crate::pbs::cons::RecordList> for UcscConservationRecordList {
        fn from(value: crate::pbs::cons::RecordList) -> Self {
            UcscConservationRecordList {
                records: value.records.into_iter().map(Into::into).collect(),
            }
        }
    }
    /// List of `ClinvarExtractedVcvRecord`s.
    #[derive(Debug, Default, Clone, serde::Serialize, serde::Deserialize, utoipa::ToSchema)]
    pub struct ExtractedVcvRecordList {
        /// The list of VCV records that may share a global variant.
        pub records: Vec<ClinvarExtractedVcvRecord>,
    }

    impl TryFrom<crate::pbs::clinvar::minimal::ExtractedVcvRecordList> for ExtractedVcvRecordList {
        type Error = anyhow::Error;

        fn try_from(
            value: crate::pbs::clinvar::minimal::ExtractedVcvRecordList,
        ) -> Result<Self, Self::Error> {
            Ok(ExtractedVcvRecordList {
                records: value
                    .records
                    .into_iter()
                    .map(TryInto::try_into)
                    .collect::<Result<_, _>>()?,
            })
        }
    }

    /// Annotation for a sinngle variant.
    #[derive(Debug, Default, Clone, serde::Serialize, serde::Deserialize, utoipa::ToSchema)]
    pub struct SeqvarsAnnoResponseRecord {
        /// Annotations from CADD (TSV annotation file).
        pub cadd: Option<indexmap::IndexMap<String, serde_json::Value>>,
        /// Annotations from dbSNP.
        pub dbsnp: Option<DbsnpRecord>,
        /// Annotations from dbNSFP (TSV annotation file).
        pub dbnsfp: Option<indexmap::IndexMap<String, serde_json::Value>>,
        /// Annotations from dbscSNV.
        pub dbscsnv: Option<indexmap::IndexMap<String, serde_json::Value>>,
        /// Annotations from gnomAD-mtDNA.
        pub gnomad_mtdna: Option<GnomadMtdnaRecord>,
        /// Annotations from gnomAD-exomes.
        pub gnomad_exomes: Option<GnomadRecord>,
        /// Annotations from gnomAD-genomes.
        pub gnomad_genomes: Option<GnomadRecord>,
        /// Annotations from HelixMTdb.
        pub helixmtdb: Option<HelixMtDbRecord>,
        /// Annotations from UCSC conservation.
        pub ucsc_conservation: Option<UcscConservationRecordList>,
        /// Minimal extracted data from ClinVar.
        pub clinvar: Option<ExtractedVcvRecordList>,
    }

    /// Query response for `handle_with_openapi()`.
    #[derive(
        Debug,
        Default,
        Clone,
        serde::Serialize,
        serde::Deserialize,
        utoipa::ToSchema,
        utoipa::ToResponse,
    )]
    pub struct SeqvarsAnnosResponse {
        /// The result records.
        pub result: SeqvarsAnnoResponseRecord,
    }
}

use response::*;

/// Query for annotations for a single variant.
#[utoipa::path(
    get,
    operation_id = "seqvarsAnosQuery",
    params(SeqvarsAnnosQuery),
    responses(
        (status = 200, description = "Annotation for a single variant.", body = SeqvarsAnnosResponse),
        (status = 500, description = "Internal server error.", body = CustomError)
    )
)]
#[get("/api/v1/genes/info")]
pub async fn handle_with_openapi(
    data: Data<crate::server::run::WebServerData>,
    _path: Path<()>,
    query: web::Query<SeqvarsAnnosQuery>,
) -> actix_web::Result<Json<SeqvarsAnnosResponse>, CustomError> {
    let genome_release = query
        .genome_release
        .parse()
        .map_err(|e: strum::ParseError| {
            CustomError::new(anyhow::anyhow!("problem getting genome release: {}", e))
        })?;

    fn json_value_to_indexmap(
        value: serde_json::Value,
    ) -> Result<indexmap::IndexMap<String, serde_json::Value>, CustomError> {
        value
            .as_object()
            .map(|v| {
                Ok(v.iter()
                    .map(|(k, v)| (k.clone(), v.clone()))
                    .collect::<indexmap::IndexMap<_, _>>())
            })
            .unwrap_or_else(|| Err(CustomError::new(anyhow::anyhow!("expected object"))))
    }

    let result = SeqvarsAnnoResponseRecord {
        cadd: data.annos[genome_release][AnnoDb::Cadd]
            .as_ref()
            .map(|db| {
                fetch_var_tsv_json(
                    &db.data,
                    AnnoDb::Cadd.cf_name(),
                    query.clone().into_inner().into(),
                )
            })
            .transpose()?
            .flatten()
            .map(json_value_to_indexmap)
            .transpose()?,
        dbsnp: data.annos[genome_release][AnnoDb::Dbsnp]
            .as_ref()
            .map(|db| {
                fetch_var_protobuf::<crate::dbsnp::pbs::Record>(
                    &db.data,
                    AnnoDb::Dbsnp.cf_name(),
                    query.clone().into_inner().into(),
                )
            })
            .transpose()?
            .flatten()
            .map(Into::into),
        dbnsfp: data.annos[genome_release][AnnoDb::Dbnsfp]
            .as_ref()
            .map(|db| {
                fetch_var_tsv_json(
                    &db.data,
                    AnnoDb::Dbnsfp.cf_name(),
                    query.clone().into_inner().into(),
                )
            })
            .transpose()?
            .flatten()
            .map(json_value_to_indexmap)
            .transpose()?,
        dbscsnv: data.annos[genome_release][AnnoDb::Dbscsnv]
            .as_ref()
            .map(|db| {
                fetch_var_tsv_json(
                    &db.data,
                    AnnoDb::Dbscsnv.cf_name(),
                    query.clone().into_inner().into(),
                )
            })
            .transpose()?
            .flatten()
            .map(json_value_to_indexmap)
            .transpose()?,
        gnomad_mtdna: data.annos[genome_release][AnnoDb::GnomadMtdna]
            .as_ref()
            .map(|db| {
                fetch_var_protobuf::<crate::pbs::gnomad::mtdna::Record>(
                    &db.data,
                    AnnoDb::GnomadMtdna.cf_name(),
                    query.clone().into_inner().into(),
                )?
                .map(TryInto::<GnomadMtdnaRecord>::try_into)
                .transpose()
                .map_err(CustomError::new)
            })
            .transpose()?
            .flatten()
            .map(Into::into),
        // gnomad_exomes: Option<bool>,
        // gnomad_genomes: Option<bool>,
        helixmtdb: data.annos[genome_release][AnnoDb::Helixmtdb]
            .as_ref()
            .map(|db| {
                Ok(fetch_var_protobuf::<crate::pbs::helixmtdb::Record>(
                    &db.data,
                    AnnoDb::Helixmtdb.cf_name(),
                    query.clone().into_inner().into(),
                )?
                .map(Into::into))
            })
            .transpose()?
            .flatten(),
        ucsc_conservation: data.annos[genome_release][AnnoDb::UcscConservation]
            .as_ref()
            .map(|db| {
                let start: keys::Pos = query.clone().into_inner().into();
                let start = keys::Pos {
                    chrom: start.chrom,
                    pos: start.pos - 2,
                };
                let stop = query.clone().into_inner().into();
                Ok(fetch_pos_protobuf::<crate::pbs::cons::RecordList>(
                    &db.data,
                    AnnoDb::UcscConservation.cf_name(),
                    start,
                    stop,
                )?
                .into_iter()
                .next()
                .map(Into::into))
            })
            .transpose()?
            .flatten(),
        clinvar: data.annos[genome_release][AnnoDb::Clinvar]
            .as_ref()
            .map(|db| {
                fetch_var_protobuf::<crate::pbs::clinvar::minimal::ExtractedVcvRecordList>(
                    &db.data,
                    AnnoDb::Clinvar.cf_name(),
                    query.clone().into_inner().into(),
                )?
                .map(TryInto::<ExtractedVcvRecordList>::try_into)
                .transpose()
                .map_err(CustomError::new)
            })
            .transpose()?
            .flatten(),
        ..Default::default()
    };

    Ok(Json(SeqvarsAnnosResponse { result }))
}