Dev

v03_pipeline/bin/vep-110-GRCh38.sh

@@ -12,7 +12,7 @@ export PROJECT="$(gcloud config get-value project)"
 export VEP_CONFIG_PATH="$(/usr/share/google/get_metadata_value attributes/VEP_CONFIG_PATH)"
 export VEP_REPLICATE="$(/usr/share/google/get_metadata_value attributes/VEP_REPLICATE)"
 export ASSEMBLY=GRCh38
-export VEP_DOCKER_IMAGE=gcr.io/seqr-project/vep-docker-image:110
+export VEP_DOCKER_IMAGE=gcr.io/seqr-project/vep-docker-image:GRCh38
 
 mkdir -p /vep_data
 
@@ -36,26 +36,26 @@ sleep 60
 sudo service docker restart
 
 # Copied from the repo at v03_pipeline/var/vep_config
-gcloud storage cp --billing-project $PROJECT gs://seqr-reference-data/vep/110/vep-${ASSEMBLY}.json $VEP_CONFIG_PATH
+gcloud storage cp --billing-project $PROJECT gs://seqr-reference-data/vep/GRCh38/vep-${ASSEMBLY}.json $VEP_CONFIG_PATH
 
 # Copied from the UTRAnnotator repo (https://github.com/ImperialCardioGenetics/UTRannotator/tree/master)
-gcloud storage cp --billing-project $PROJECT gs://seqr-reference-data/vep/110/uORF_5UTR_${ASSEMBLY}_PUBLIC.txt /vep_data/ &
+gcloud storage cp --billing-project $PROJECT gs://seqr-reference-data/vep/GRCh38/uORF_5UTR_${ASSEMBLY}_PUBLIC.txt /vep_data/ &
 
 # Raw data files copied from the bucket (https://console.cloud.google.com/storage/browser/dm_alphamissense;tab=objects?prefix=&forceOnObjectsSortingFiltering=false)
 # tabix -s 1 -b 2 -e 2 -f -S 1 AlphaMissense_hg38.tsv.gz
-gcloud storage cp --billing-project $PROJECT 'gs://seqr-reference-data/vep/110/AlphaMissense_hg38.tsv.*' /vep_data/ &
+gcloud storage cp --billing-project $PROJECT 'gs://seqr-reference-data/vep/GRCh38/AlphaMissense_hg38.tsv.*' /vep_data/ &
 
 gcloud storage cat --billing-project $PROJECT gs://seqr-reference-data/vep_data/loftee-beta/${ASSEMBLY}.tar | tar -xf - -C /vep_data/ &
 
 # Copied from ftp://ftp.ensembl.org/pub/release-110/variation/indexed_vep_cache/homo_sapiens_vep_110_${ASSEMBLY}.tar.gz
-gcloud storage cat --billing-project $PROJECT gs://seqr-reference-data/vep/110/homo_sapiens_vep_110_${ASSEMBLY}.tar.gz | tar -xzf - -C /vep_data/ &
+gcloud storage cat --billing-project $PROJECT gs://seqr-reference-data/vep/GRCh38/homo_sapiens_vep_110_${ASSEMBLY}.tar.gz | tar -xzf - -C /vep_data/ &
 
 # Generated with:
 # curl -O ftp://ftp.ensembl.org/pub/release-110/fasta/homo_sapiens/dna/Homo_sapiens.${ASSEMBLY}.dna.primary_assembly.fa.gz > Homo_sapiens.${ASSEMBLY}.dna.primary_assembly.fa.gz
 # gzip -d Homo_sapiens.${ASSEMBLY}.dna.primary_assembly.fa.gz
 # bgzip Homo_sapiens.${ASSEMBLY}.dna.primary_assembly.fa
 # samtools faidx Homo_sapiens.${ASSEMBLY}.dna.primary_assembly.fa.gz
-gcloud storage cp --billing-project $PROJECT "gs://seqr-reference-data/vep/110/Homo_sapiens.${ASSEMBLY}.dna.primary_assembly.fa.*" /vep_data/ &
+gcloud storage cp --billing-project $PROJECT "gs://seqr-reference-data/vep/GRCh38/Homo_sapiens.${ASSEMBLY}.dna.primary_assembly.fa.*" /vep_data/ &
 docker pull ${VEP_DOCKER_IMAGE} &
 wait
 

v03_pipeline/lib/model/reference_dataset_collection.py

@@ -45,6 +45,7 @@ def datasets(self, dataset_type: DatasetType) -> list[str]:
                 'hmtvar',
                 'mitomap',
                 'mitimpact',
+                'local_constraint_mito',
             ],
             (ReferenceDatasetCollection.HGMD, DatasetType.SNV_INDEL): ['hgmd'],
             (ReferenceDatasetCollection.INTERVAL, DatasetType.SNV_INDEL): [

v03_pipeline/lib/reference_data/config.py

@@ -16,6 +16,9 @@
     parsed_clnsig,
 )
 from v03_pipeline.lib.reference_data.hgmd import download_and_import_hgmd_vcf
+from v03_pipeline.lib.reference_data.mito import (
+    download_and_import_local_constraint_tsv,
+)
 
 
 def import_locus_intervals(
@@ -533,4 +536,14 @@ def custom_mpc_select(ht):
             'custom_import': import_locus_intervals,
         },
     },
+    'local_constraint_mito': {
+        '38': {
+            'version': '2024-07-24',
+            # Originally sourced from https://www.biorxiv.org/content/10.1101/2022.12.16.520778v2.supplementary-material
+            # Supplementary Table 7.
+            'source_path': 'gs://seqr-reference-data/GRCh38/mitochondrial/local_constraint.tsv',
+            'custom_import': download_and_import_local_constraint_tsv,
+            'select': {'score': 'MLC_score'},
+        },
+    },
 }

v03_pipeline/lib/reference_data/mito.py

@@ -0,0 +1,16 @@
+import hail as hl
+
+from v03_pipeline.lib.model.definitions import ReferenceGenome
+
+
+def download_and_import_local_constraint_tsv(
+    url: str,
+    reference_genome: ReferenceGenome,
+) -> hl.Table:
+    ht = hl.import_table(url, types={'Position': hl.tint32, 'MLC_score': hl.tfloat32})
+    ht = ht.select(
+        locus=hl.locus('chrM', ht.Position, reference_genome.value),
+        alleles=[ht.Reference, ht.Alternate],
+        MLC_score=ht.MLC_score,
+    )
+    return ht.key_by('locus', 'alleles')

v03_pipeline/lib/tasks/reference_data/update_variant_annotations_table_with_updated_reference_dataset_test.py

@@ -628,6 +628,21 @@
             ),
         },
     },
+    'local_constraint_mito': {
+        '38': {
+            **CONFIG['local_constraint_mito']['38'],
+            'custom_import': lambda *_: hl.Table.parallelize(
+                [],
+                hl.tstruct(
+                    locus=hl.tlocus('GRCh38'),
+                    alleles=hl.tarray(hl.tstr),
+                    MLC_score=hl.tfloat32,
+                ),
+                key=['locus', 'alleles'],
+                globals=hl.Struct(),
+            ),
+        },
+    },
 }
 
 
@@ -960,6 +975,7 @@ def test_update_vat_with_updated_rdc_mito_38(
                         clinvar_mito='ftp://ftp.ncbi.nlm.nih.gov/pub/clinvar/vcf_GRCh38/clinvar.vcf.gz',
                         dbnsfp_mito='gs://seqr-reference-data/GRCh38/dbNSFP/v4.2/dbNSFP4.2a_variant.with_new_scores.ht',
                         high_constraint_region_mito='gs://seqr-reference-data/GRCh38/mitochondrial/Helix high constraint intervals Feb-15-2022.tsv',
+                        local_constraint_mito='gs://seqr-reference-data/GRCh38/mitochondrial/local_constraint.tsv',
                     ),
                     versions=hl.Struct(
                         gnomad_mito='v3.1',
@@ -970,6 +986,7 @@ def test_update_vat_with_updated_rdc_mito_38(
                         clinvar_mito='2023-07-22',
                         dbnsfp_mito='4.2',
                         high_constraint_region_mito='Feb-15-2022',
+                        local_constraint_mito='2024-07-24',
                     ),
                     enums=hl.Struct(
                         gnomad_mito=hl.Struct(),
@@ -985,6 +1002,7 @@ def test_update_vat_with_updated_rdc_mito_38(
                             MutationTaster_pred=['D', 'A', 'N', 'P'],
                         ),
                         high_constraint_region_mito=hl.Struct(),
+                        local_constraint_mito=hl.Struct(),
                         sorted_transcript_consequences=hl.Struct(
                             biotype=BIOTYPES,
                             consequence_term=TRANSCRIPT_CONSEQUENCE_TERMS,
@@ -1041,6 +1059,7 @@ def test_update_vat_with_updated_rdc_mito_38(
                     mitomap=None,
                     mitimpact=hl.Struct(score=0.5199999809265137),
                     high_constraint_region_mito=True,
+                    local_constraint_mito=hl.Struct(score=0.5),
                 ),
             ],
         )

v03_pipeline/lib/tasks/update_variant_annotations_table_with_new_samples_test.py

@@ -842,6 +842,7 @@ def test_mito_update_vat(
                         hmtvar='gs://seqr-reference-data/GRCh38/mitochondrial/HmtVar/HmtVar%20Jan.%2010%202022.ht',
                         mitomap='gs://seqr-reference-data/GRCh38/mitochondrial/MITOMAP/mitomap-confirmed-mutations-2022-02-04.ht',
                         mitimpact='gs://seqr-reference-data/GRCh38/mitochondrial/MitImpact/MitImpact_db_3.0.7.ht',
+                        local_constraint_mito='gs://seqr-reference-data/GRCh38/mitochondrial/local_constraint.tsv',
                     ),
                     versions=hl.Struct(
                         high_constraint_region_mito='Feb-15-2022',
@@ -852,9 +853,11 @@ def test_mito_update_vat(
                         hmtvar='Jan. 10 2022',
                         mitomap='Feb. 04 2022',
                         mitimpact='3.0.7',
+                        local_constraint_mito='2024-07-24',
                     ),
                     enums=hl.Struct(
                         high_constraint_region_mito=hl.Struct(),
+                        local_constraint_mito=hl.Struct(),
                         clinvar_mito=hl.Struct(
                             assertion=CLINVAR_ASSERTIONS,
                             pathogenicity=CLINVAR_PATHOGENICITIES,
@@ -920,6 +923,7 @@ def test_mito_update_vat(
                         AF_hom=0.0,
                         AN=4,
                     ),
+                    local_constraint_mito=None,
                 ),
                 hl.Struct(
                     locus=hl.Locus(
@@ -955,6 +959,7 @@ def test_mito_update_vat(
                         AF_hom=0.0,
                         AN=4,
                     ),
+                    local_constraint_mito=None,
                 ),
                 hl.Struct(
                     locus=hl.Locus(
@@ -990,6 +995,7 @@ def test_mito_update_vat(
                         AF_hom=0.0,
                         AN=4,
                     ),
+                    local_constraint_mito=None,
                 ),
                 hl.Struct(
                     locus=hl.Locus(
@@ -1025,6 +1031,7 @@ def test_mito_update_vat(
                         AF_hom=0.0,
                         AN=4,
                     ),
+                    local_constraint_mito=None,
                 ),
                 hl.Struct(
                     locus=hl.Locus(
@@ -1060,6 +1067,7 @@ def test_mito_update_vat(
                         AF_hom=0.0,
                         AN=4,
                     ),
+                    local_constraint_mito=None,
                 ),
             ],
         )

v03_pipeline/var/test/reference_data/test_combined_mito_1.ht/README.txt

@@ -1,3 +1,3 @@
 This folder comprises a Hail (www.hail.is) native Table or MatrixTable.
   Written with version 0.2.130-bea04d9c79b5
-  Created at 2024/05/20 14:08:17
+  Created at 2024/07/24 14:11:11