mehari 0.45.1

Variant effect prediction all in Rust
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
241

use crate::annotate::seqvars::consequence::VcfVariant;
use crate::common::contig::ContigManager;
use crate::db::keys;
use annonars::freqs::serialized::{auto, mt, xy};
use anyhow::Error;
use rocksdb::{DBWithThreadMode, MultiThreaded};
use serde::{Deserialize, Serialize};
use std::fmt::Display;
use std::path::Path;
use std::sync::Arc;

#[derive(Debug)]
pub struct FrequencyAnnotator {
    db: DBWithThreadMode<MultiThreaded>,
    contig_manager: Arc<ContigManager>,
}

impl FrequencyAnnotator {
    pub fn new(db: DBWithThreadMode<MultiThreaded>, contig_manager: Arc<ContigManager>) -> Self {
        Self { db, contig_manager }
    }

    pub(crate) fn from_path(
        path: impl AsRef<Path> + Display,
        contig_manager: Arc<ContigManager>,
    ) -> anyhow::Result<Self> {
        // Open the frequency RocksDB database in read only mode.
        tracing::info!("Opening frequency database");
        tracing::debug!("RocksDB path = {}", &path);
        let options = rocksdb::Options::default();
        let db_freq = rocksdb::DB::open_cf_for_read_only(
            &options,
            &path,
            ["meta", "autosomal", "gonosomal", "mitochondrial"],
            false,
        )?;
        Ok(Self::new(db_freq, contig_manager))
    }

    /// Annotate record on autosomal chromosome with gnomAD exomes/genomes.
    pub fn annotate_record_auto(&self, key: &[u8]) -> Result<Option<FreqResult>, Error> {
        if let Some(freq) = self
            .db
            .get_cf(self.db.cf_handle("autosomal").as_ref().unwrap(), key)?
        {
            let auto_record = auto::Record::from_buf(&freq);
            Ok(Some(FreqResult {
                gnomad_exomes_an: auto_record.gnomad_exomes.an as i32,
                gnomad_exomes_hom: auto_record.gnomad_exomes.ac_hom as i32,
                gnomad_exomes_het: auto_record.gnomad_exomes.ac_het as i32,
                gnomad_genomes_an: auto_record.gnomad_genomes.an as i32,
                gnomad_genomes_hom: auto_record.gnomad_genomes.ac_hom as i32,
                gnomad_genomes_het: auto_record.gnomad_genomes.ac_het as i32,
                ..Default::default()
            }))
        } else {
            Ok(None)
        }
    }

    /// Annotate record on gonosomal chromosome with gnomAD exomes/genomes.
    pub fn annotate_record_xy(&self, key: &[u8]) -> Result<Option<FreqResult>, Error> {
        if let Some(freq) = self
            .db
            .get_cf(self.db.cf_handle("gonosomal").as_ref().unwrap(), key)?
        {
            let xy_record = xy::Record::from_buf(&freq);
            Ok(Some(FreqResult {
                gnomad_exomes_an: xy_record.gnomad_exomes.an as i32,
                gnomad_exomes_hom: xy_record.gnomad_exomes.ac_hom as i32,
                gnomad_exomes_het: xy_record.gnomad_exomes.ac_het as i32,
                gnomad_exomes_hemi: Some(xy_record.gnomad_exomes.ac_hemi as i32),
                gnomad_genomes_an: xy_record.gnomad_genomes.an as i32,
                gnomad_genomes_hom: xy_record.gnomad_genomes.ac_hom as i32,
                gnomad_genomes_het: xy_record.gnomad_genomes.ac_het as i32,
                gnomad_genomes_hemi: Some(xy_record.gnomad_genomes.ac_hemi as i32),
                ..Default::default()
            }))
        } else {
            Ok(None)
        }
    }

    /// Annotate record on mitochondrial genome with gnomAD mtDNA and HelixMtDb.
    pub fn annotate_record_mt(&self, key: &[u8]) -> Result<Option<FreqResult>, Error> {
        if let Some(freq) = self
            .db
            .get_cf(self.db.cf_handle("mitochondrial").as_ref().unwrap(), key)?
        {
            let mt_record = mt::Record::from_buf(&freq);
            Ok(Some(FreqResult {
                helix_an: Some(mt_record.helixmtdb.an as i32),
                helix_hom: Some(mt_record.helixmtdb.ac_hom as i32),
                helix_het: Some(mt_record.helixmtdb.ac_het as i32),
                gnomad_genomes_an: mt_record.gnomad_mtdna.an as i32,
                gnomad_genomes_hom: mt_record.gnomad_mtdna.ac_hom as i32,
                gnomad_genomes_het: mt_record.gnomad_mtdna.ac_het as i32,
                ..Default::default()
            }))
        } else {
            Ok(None)
        }
    }

    pub(crate) fn annotate(&self, vcf_var: &keys::Var) -> anyhow::Result<Option<FreqResult>> {
        let contig_manager = &self.contig_manager;
        // Only attempt lookups into RocksDB for canonical contigs.
        if contig_manager.is_homo_sapiens_canonical_alias(vcf_var.chrom.as_str()) {
            // Build key for RocksDB database from `vcf_var`.
            let annonars_var: annonars::common::keys::Var = vcf_var.into();
            let key: Vec<u8> = annonars_var.into();

            // Annotate with frequency.
            if contig_manager.is_autosomal_alias(&vcf_var.chrom) {
                return self.annotate_record_auto(&key);
            } else if contig_manager.is_gonosomal_alias(&vcf_var.chrom) {
                return self.annotate_record_xy(&key);
            } else if contig_manager.is_mitochondrial_alias(&vcf_var.chrom) {
                return self.annotate_record_mt(&key);
            }
        }
        Ok(None)
    }

    #[cfg(feature = "server")]
    pub(crate) fn annotate_variant(
        &self,
        vcf_var: &VcfVariant,
    ) -> anyhow::Result<
        Option<crate::server::run::actix_server::seqvars_frequencies::FrequencyResultEntry>,
    > {
        let contig_manager = &self.contig_manager;
        // Only attempt lookups into RocksDB for canonical contigs.
        if !contig_manager.is_homo_sapiens_canonical_alias(&vcf_var.chromosome) {
            return Ok(None);
        }

        // Build key for RocksDB database
        let vcf_var = annonars::common::keys::Var::from(
            &vcf_var.chromosome.clone(),
            vcf_var.position,
            &vcf_var.reference.clone(),
            &vcf_var.alternative.clone(),
        );
        let key: Vec<u8> = vcf_var.clone().into();
        use crate::server::run::actix_server::seqvars_frequencies::*;
        use anyhow::anyhow;
        // Annotate with frequency.
        if contig_manager.is_autosomal_alias(vcf_var.chrom.as_str()) {
            match self
                .db
                .get_cf(self.db.cf_handle("autosomal").as_ref().unwrap(), key)?
            {
                Some(freq) => {
                    let val = auto::Record::from_buf(&freq);
                    Ok(Some(FrequencyResultEntry::Autosomal(
                        AutosomalResultEntry {
                            gnomad_exomes_an: val.gnomad_exomes.an,
                            gnomad_exomes_hom: val.gnomad_exomes.ac_hom,
                            gnomad_exomes_het: val.gnomad_exomes.ac_het,
                            gnomad_genomes_an: val.gnomad_genomes.an,
                            gnomad_genomes_hom: val.gnomad_genomes.ac_hom,
                            gnomad_genomes_het: val.gnomad_genomes.ac_het,
                        },
                    )))
                }
                _ => Err(anyhow!("No frequency data found for variant {:?}", vcf_var)),
            }
        } else if contig_manager.is_gonosomal_alias(vcf_var.chrom.as_str()) {
            match self
                .db
                .get_cf(self.db.cf_handle("gonosomal").as_ref().unwrap(), key)?
            {
                Some(freq) => {
                    let val = xy::Record::from_buf(&freq);
                    Ok(Some(FrequencyResultEntry::Gonosomal(
                        GonosomalResultEntry {
                            gnomad_exomes_an: val.gnomad_exomes.an,
                            gnomad_exomes_hom: val.gnomad_exomes.ac_hom,
                            gnomad_exomes_het: val.gnomad_exomes.ac_het,
                            gnomad_exomes_hemi: val.gnomad_exomes.ac_hemi,
                            gnomad_genomes_an: val.gnomad_genomes.an,
                            gnomad_genomes_hom: val.gnomad_genomes.ac_hom,
                            gnomad_genomes_het: val.gnomad_genomes.ac_het,
                            gnomad_genomes_hemi: val.gnomad_genomes.ac_hemi,
                        },
                    )))
                }
                _ => Err(anyhow!("No frequency data found for variant {:?}", vcf_var)),
            }
        } else if contig_manager.is_mitochondrial_alias(vcf_var.chrom.as_str()) {
            match self
                .db
                .get_cf(self.db.cf_handle("mitochondrial").as_ref().unwrap(), key)?
            {
                Some(freq) => {
                    let val = mt::Record::from_buf(&freq);
                    Ok(Some(FrequencyResultEntry::Mitochondrial(
                        MitochondrialResultEntry {
                            helix_an: val.helixmtdb.an,
                            helix_hom: val.helixmtdb.ac_hom,
                            helix_het: val.helixmtdb.ac_het,
                            gnomad_genomes_an: val.gnomad_mtdna.an,
                            gnomad_genomes_hom: val.gnomad_mtdna.ac_hom,
                            gnomad_genomes_het: val.gnomad_mtdna.ac_het,
                        },
                    )))
                }
                _ => Err(anyhow!("No frequency data found for variant {:?}", vcf_var)),
            }
        } else {
            tracing::trace!(
                "Record @{:?} on non-canonical chromosome, skipping.",
                &vcf_var
            );
            Ok(None)
        }
    }
}

#[derive(Debug, Clone, Default, Serialize, Deserialize)]
pub struct FreqResult {
    pub gnomad_exomes_an: i32,
    pub gnomad_exomes_hom: i32,
    pub gnomad_exomes_het: i32,
    #[serde(skip_serializing_if = "Option::is_none")]
    pub gnomad_exomes_hemi: Option<i32>,

    pub gnomad_genomes_an: i32,
    pub gnomad_genomes_hom: i32,
    pub gnomad_genomes_het: i32,
    #[serde(skip_serializing_if = "Option::is_none")]
    pub gnomad_genomes_hemi: Option<i32>,

    #[serde(skip_serializing_if = "Option::is_none")]
    pub helix_an: Option<i32>,
    #[serde(skip_serializing_if = "Option::is_none")]
    pub helix_hom: Option<i32>,
    #[serde(skip_serializing_if = "Option::is_none")]
    pub helix_het: Option<i32>,
}