From 20f7487951ce7c0945786d38db6ade83d949201f Mon Sep 17 00:00:00 2001
From: jkgoodrich <33063077+jkgoodrich@users.noreply.github.com>
Date: Tue, 30 Sep 2025 08:30:41 -0600
Subject: [PATCH 1/3] add vep 115 to the vep_context options

---
 gnomad/resources/grch38/reference_data.py | 3 +++
 1 file changed, 3 insertions(+)

diff --git a/gnomad/resources/grch38/reference_data.py b/gnomad/resources/grch38/reference_data.py
index 25040940f..f2edd0a39 100644
--- a/gnomad/resources/grch38/reference_data.py
+++ b/gnomad/resources/grch38/reference_data.py
@@ -156,6 +156,9 @@ def _import_ensembl_interval(path) -> hl.Table:
         "105": GnomadPublicTableResource(
             path="gs://gnomad-public-requester-pays/resources/context/grch38_context_vep_annotated.v105.ht",
         ),
+        "115": GnomadPublicTableResource(
+            path="gs://gnomad-public-requester-pays/resources/context/grch38_context_vep_annotated.v115.ht",
+        ),
     },
 )
 

From e5cacea6a09443235585f4ef8e771687af93b0a8 Mon Sep 17 00:00:00 2001
From: jkgoodrich <33063077+jkgoodrich@users.noreply.github.com>
Date: Tue, 30 Sep 2025 14:21:15 -0600
Subject: [PATCH 2/3] Add VEP 115 init

---
 init_scripts/vep115-init.sh | 101 ++++++++++++++++++++++++++++++++++++
 1 file changed, 101 insertions(+)
 create mode 100644 init_scripts/vep115-init.sh

diff --git a/init_scripts/vep115-init.sh b/init_scripts/vep115-init.sh
new file mode 100644
index 000000000..3aeae3d05
--- /dev/null
+++ b/init_scripts/vep115-init.sh
@@ -0,0 +1,101 @@
+#!/bin/bash
+
+export PROJECT="$(gcloud config get-value project)"
+export VEP_CONFIG_PATH="$(/usr/share/google/get_metadata_value attributes/VEP_CONFIG_PATH)"
+export VEP_REPLICATE="$(/usr/share/google/get_metadata_value attributes/VEP_REPLICATE)"
+export VEP_BUCKET=hail-${VEP_REPLICATE}-vep
+export ASSEMBLY=GRCh38
+export VEP_DOCKER_IMAGE=us-central1-docker.pkg.dev/broad-mpg-gnomad/images/vep115
+
+mkdir -p /vep_data/loftee_data
+mkdir -p /vep_data/homo_sapiens
+
+# Install docker
+apt-get update
+apt-get -y install \
+    apt-transport-https \
+    ca-certificates \
+    curl \
+    gnupg2 \
+    software-properties-common \
+    tabix
+curl -fsSL https://download.docker.com/linux/debian/gpg | sudo apt-key add -
+sudo add-apt-repository "deb [arch=amd64] https://download.docker.com/linux/debian $(lsb_release -cs) stable"
+apt-get update
+apt-get install -y --allow-unauthenticated docker-ce
+
+
+gsutil -u ${PROJECT} cat gs://${VEP_BUCKET}/loftee-beta/${ASSEMBLY}.tar | tar -xf - -C /vep_data/
+
+docker pull ${VEP_DOCKER_IMAGE}
+
+
+################################################################
+# Added stuff
+################################################################
+
+# GCS copy of https://ftp.ebi.ac.uk/ensemblorg/pub/release-115/variation/indexed_vep_cache/homo_sapiens_merged_vep_115_GRCh38.tar.gz
+gsutil -u $PROJECT cat gs://gcp-public-data--gnomad/resources/vep/v115/homo_sapiens_merged_vep_115_GRCh38.tar.gz | tar -xzf - -C /vep_data
+
+
+# FASTA file from Hail's VEP 95 data
+gsutil -u "$PROJECT" cp gs://gcp-public-data--gnomad/resources/vep/Homo_sapiens.GRCh38.dna.toplevel.fa.gz /vep_data/
+gsutil -u $PROJECT cp gs://gcp-public-data--gnomad/resources/vep/Homo_sapiens.GRCh38.dna.toplevel.fa.gz.fai /vep_data/
+gsutil -u $PROJECT cp gs://gcp-public-data--gnomad/resources/vep/Homo_sapiens.GRCh38.dna.toplevel.fa.gz.gzi /vep_data/
+
+# Create config file.
+cat > /vep_data/vep115-GRCh38.json <<EOF
+{"command": [
+    "/vep",
+    "--format", "vcf",
+    "__OUTPUT_FORMAT_FLAG__",
+    "--everything",
+    "--allele_number",
+    "--no_stats",
+    "--regulatory",
+    "--cache", "--offline",
+    "--minimal",
+    "--assembly", "GRCh38",
+    "--merged",
+    "--fasta", "/opt/vep/.vep/Homo_sapiens.GRCh38.dna.toplevel.fa.gz",
+    "--plugin", "LoF,loftee_path:/opt/vep/Plugins,gerp_bigwig:/opt/vep/.vep/gerp_conservation_scores.homo_sapiens.GRCh38.bw,human_ancestor_fa:/opt/vep/.vep/human_ancestor.fa.gz,conservation_file:/opt/vep/.vep/loftee.sql",
+    "--plugin", "context",
+    "--plugin", "ancestral,human_ancestor_fa:/opt/vep/.vep/human_ancestor.fa.gz",
+    "--dir_plugins", "/opt/vep/Plugins/",
+    "-o", "STDOUT"
+],
+ "env": {},
+"vep_json_schema": "Struct{allele_string:String,assembly_name:String,colocated_variants:Array[Struct{allele_string:String,clin_sig:Array[String],clin_sig_allele:String,end:Int32,evidence:Array[String],id:String,minor_allele:String,minor_allele_freq:Float64,phenotype_or_disease:Int32,phenotypes:Array[String],pubmed:Array[String],somatic:Int32,seq_region_name:String,start:Int32,strand:Int32}],end:Int32,id:String,input:String,intergenic_consequences:Array[Struct{allele_num:Int32,ancestral:String,consequence_terms:Array[String],context:String,impact:String,variant_allele:String}],minimised:Int32,most_severe_consequence:String,motif_feature_consequences:Array[Struct{allele_num:Int32,biotype:String,consequence_terms:Array[String],high_inf_pos:String,impact:String,motif_feature_id:String,motif_name:String,motif_pos:Int32,motif_score_change:Float64,transcription_factors:Array[String],strand:Int32,variant_allele:String}],regulatory_feature_consequences:Array[Struct{allele_num:Int32,ancestral:String,biotype:String,consequence_terms:Array[String],context:String,impact:String,regulatory_feature_id:String,variant_allele:String}],seq_region_name:String,start:Int32,strand:Int32,transcript_consequences:Array[Struct{allele_num:Int32,amino_acids:String,ancestral:String,appris:String,bam_edit:String,biotype:String,canonical:Int32,ccds:String,cdna_start:Int32,cdna_end:Int32,cds_end:Int32,cds_start:Int32,codons:String,consequence_terms:Array[String],context:String,distance:Int32,domains:Array[Struct{db:String,name:String}],exon:String,gene_id:String,gene_pheno:Int32,gene_symbol:String,gene_symbol_source:String,given_ref:String,hgnc_id:String,hgvsc:String,hgvsp:String,hgvs_offset:Int32,impact:String,intron:String,lof:String,lof_filter:String,lof_flags:String,lof_info:String,mane:Array[String],mane_select:String,mane_plus_clinical:String,polyphen_prediction:String,polyphen_score:Float64,protein_end:Int32,protein_id:String,protein_start:Int32,sift_prediction:String,sift_score:Float64,source:String,strand:Int32,swissprot:Array[String],transcript_id:String,trembl:Array[String],tsl:String,uniparc:Array[String],uniprot_isoform:Array[String],used_ref:String,variant_allele:String}],variant_class:String}"
+}
+EOF
+
+ln -s /vep_data/vep115-GRCh38.json $VEP_CONFIG_PATH
+
+
+################################################################
+# End added stuff
+################################################################
+
+cat >/vep.c <<EOF
+#include <unistd.h>
+#include <stdio.h>
+
+int
+main(int argc, char *const argv[]) {
+  if (setuid(geteuid()))
+    perror( "setuid" );
+
+  execv("/vep.sh", argv);
+  return 0;
+}
+EOF
+gcc -Wall -Werror -O2 /vep.c -o /vep
+chmod u+s /vep
+
+cat >/vep.sh <<EOF
+#!/bin/bash
+
+docker run -i -v /vep_data/:/opt/vep/.vep/:ro ${VEP_DOCKER_IMAGE} \
+  /opt/vep/src/ensembl-vep/vep "\$@"
+EOF
+chmod +x /vep.sh

From a016c567293410634c875d5608bc00e87cc2993f Mon Sep 17 00:00:00 2001
From: jkgoodrich <33063077+jkgoodrich@users.noreply.github.com>
Date: Thu, 2 Oct 2025 13:46:13 -0600
Subject: [PATCH 3/3] Update vep115 init after testing

---
 init_scripts/vep115-init.sh | 43 ++++++++++++++++++++++++-------------
 1 file changed, 28 insertions(+), 15 deletions(-)

diff --git a/init_scripts/vep115-init.sh b/init_scripts/vep115-init.sh
index 3aeae3d05..492ee7f3b 100644
--- a/init_scripts/vep115-init.sh
+++ b/init_scripts/vep115-init.sh
@@ -7,9 +7,6 @@ export VEP_BUCKET=hail-${VEP_REPLICATE}-vep
 export ASSEMBLY=GRCh38
 export VEP_DOCKER_IMAGE=us-central1-docker.pkg.dev/broad-mpg-gnomad/images/vep115
 
-mkdir -p /vep_data/loftee_data
-mkdir -p /vep_data/homo_sapiens
-
 # Install docker
 apt-get update
 apt-get -y install \
@@ -25,11 +22,11 @@ apt-get update
 apt-get install -y --allow-unauthenticated docker-ce
 
 
-gsutil -u ${PROJECT} cat gs://${VEP_BUCKET}/loftee-beta/${ASSEMBLY}.tar | tar -xf - -C /vep_data/
+mkdir -p /vep_data/loftee_data
+gsutil -u ${PROJECT} cat gs://${VEP_BUCKET}/loftee-beta/${ASSEMBLY}.tar | tar -xf - -C /vep_data/loftee_data &
 
 docker pull ${VEP_DOCKER_IMAGE}
 
-
 ################################################################
 # Added stuff
 ################################################################
@@ -38,7 +35,7 @@ docker pull ${VEP_DOCKER_IMAGE}
 gsutil -u $PROJECT cat gs://gcp-public-data--gnomad/resources/vep/v115/homo_sapiens_merged_vep_115_GRCh38.tar.gz | tar -xzf - -C /vep_data
 
 
-# FASTA file from Hail's VEP 95 data
+# FASTA file for GRCh38.
 gsutil -u "$PROJECT" cp gs://gcp-public-data--gnomad/resources/vep/Homo_sapiens.GRCh38.dna.toplevel.fa.gz /vep_data/
 gsutil -u $PROJECT cp gs://gcp-public-data--gnomad/resources/vep/Homo_sapiens.GRCh38.dna.toplevel.fa.gz.fai /vep_data/
 gsutil -u $PROJECT cp gs://gcp-public-data--gnomad/resources/vep/Homo_sapiens.GRCh38.dna.toplevel.fa.gz.gzi /vep_data/
@@ -49,23 +46,39 @@ cat > /vep_data/vep115-GRCh38.json <<EOF
     "/vep",
     "--format", "vcf",
     "__OUTPUT_FORMAT_FLAG__",
-    "--everything",
+    "--assembly", "GRCh38",
+    "--fasta", "/opt/vep/.vep/Homo_sapiens.GRCh38.dna.toplevel.fa.gz",
+    "--merged",
+    "--cache", "--offline",
+    "--sift", "b",
+    "--polyphen", "b",
+    "--ccds",
+    "--hgvs",
+    "--symbol",
+    "--numbers",
+    "--domains",
+    "--regulatory",
+    "--canonical",
+    "--protein",
+    "--biotype",
+    "--pubmed",
+    "--uniprot",
+    "--mane",
+    "--tsl",
+    "--appris",
+    "--variant_class",
+    "--gene_phenotype",
+    "--mirna",
     "--allele_number",
     "--no_stats",
-    "--regulatory",
-    "--cache", "--offline",
     "--minimal",
-    "--assembly", "GRCh38",
-    "--merged",
-    "--fasta", "/opt/vep/.vep/Homo_sapiens.GRCh38.dna.toplevel.fa.gz",
-    "--plugin", "LoF,loftee_path:/opt/vep/Plugins,gerp_bigwig:/opt/vep/.vep/gerp_conservation_scores.homo_sapiens.GRCh38.bw,human_ancestor_fa:/opt/vep/.vep/human_ancestor.fa.gz,conservation_file:/opt/vep/.vep/loftee.sql",
     "--plugin", "context",
-    "--plugin", "ancestral,human_ancestor_fa:/opt/vep/.vep/human_ancestor.fa.gz",
+    "--plugin", "LoF,loftee_path:/opt/vep/Plugins,gerp_bigwig:/opt/vep/.vep/loftee_data/gerp_conservation_scores.homo_sapiens.GRCh38.bw,human_ancestor_fa:/opt/vep/.vep/loftee_data/human_ancestor.fa.gz,conservation_file:/opt/vep/.vep/loftee_data/loftee.sql",
     "--dir_plugins", "/opt/vep/Plugins/",
     "-o", "STDOUT"
 ],
  "env": {},
-"vep_json_schema": "Struct{allele_string:String,assembly_name:String,colocated_variants:Array[Struct{allele_string:String,clin_sig:Array[String],clin_sig_allele:String,end:Int32,evidence:Array[String],id:String,minor_allele:String,minor_allele_freq:Float64,phenotype_or_disease:Int32,phenotypes:Array[String],pubmed:Array[String],somatic:Int32,seq_region_name:String,start:Int32,strand:Int32}],end:Int32,id:String,input:String,intergenic_consequences:Array[Struct{allele_num:Int32,ancestral:String,consequence_terms:Array[String],context:String,impact:String,variant_allele:String}],minimised:Int32,most_severe_consequence:String,motif_feature_consequences:Array[Struct{allele_num:Int32,biotype:String,consequence_terms:Array[String],high_inf_pos:String,impact:String,motif_feature_id:String,motif_name:String,motif_pos:Int32,motif_score_change:Float64,transcription_factors:Array[String],strand:Int32,variant_allele:String}],regulatory_feature_consequences:Array[Struct{allele_num:Int32,ancestral:String,biotype:String,consequence_terms:Array[String],context:String,impact:String,regulatory_feature_id:String,variant_allele:String}],seq_region_name:String,start:Int32,strand:Int32,transcript_consequences:Array[Struct{allele_num:Int32,amino_acids:String,ancestral:String,appris:String,bam_edit:String,biotype:String,canonical:Int32,ccds:String,cdna_start:Int32,cdna_end:Int32,cds_end:Int32,cds_start:Int32,codons:String,consequence_terms:Array[String],context:String,distance:Int32,domains:Array[Struct{db:String,name:String}],exon:String,gene_id:String,gene_pheno:Int32,gene_symbol:String,gene_symbol_source:String,given_ref:String,hgnc_id:String,hgvsc:String,hgvsp:String,hgvs_offset:Int32,impact:String,intron:String,lof:String,lof_filter:String,lof_flags:String,lof_info:String,mane:Array[String],mane_select:String,mane_plus_clinical:String,polyphen_prediction:String,polyphen_score:Float64,protein_end:Int32,protein_id:String,protein_start:Int32,sift_prediction:String,sift_score:Float64,source:String,strand:Int32,swissprot:Array[String],transcript_id:String,trembl:Array[String],tsl:String,uniparc:Array[String],uniprot_isoform:Array[String],used_ref:String,variant_allele:String}],variant_class:String}"
+"vep_json_schema": "Struct{allele_string:String,colocated_variants:Array[Struct{allele_string:String,clin_sig:Array[String],clin_sig_allele:String,end:Int32,id:String,phenotype_or_disease:Int32,pubmed:Array[Int32],somatic:Int32,seq_region_name:String,start:Int32,strand:Int32}],end:Int32,id:String,input:String,intergenic_consequences:Array[Struct{allele_num:Int32,consequence_terms:Array[String],context:String,impact:String,variant_allele:String}],minimised:Int32,most_severe_consequence:String,motif_feature_consequences:Array[Struct{allele_num:Int32,biotype:String,consequence_terms:Array[String],high_inf_pos:String,impact:String,motif_feature_id:String,motif_name:String,motif_pos:Int32,motif_score_change:Float64,transcription_factors:Array[String],strand:Int32,variant_allele:String}],regulatory_feature_consequences:Array[Struct{allele_num:Int32,biotype:String,consequence_terms:Array[String],context:String,impact:String,regulatory_feature_id:String,variant_allele:String}],seq_region_name:String,start:Int32,strand:Int32,transcript_consequences:Array[Struct{allele_num:Int32,amino_acids:String,appris:String,bam_edit:String,biotype:String,canonical:Int32,ccds:String,cdna_start:Int32,cdna_end:Int32,cds_end:Int32,cds_start:Int32,codons:String,consequence_terms:Array[String],context:String,distance:Int32,domains:Array[Struct{db:String,name:String}],exon:String,flags:String,gene_id:String,gene_pheno:Int32,gene_symbol:String,gene_symbol_source:String,given_ref:String,hgnc_id:String,hgvsc:String,hgvsp:String,hgvs_offset:Int32,impact:String,intron:String,lof:String,lof_filter:String,lof_flags:String,lof_info:String,mane:Array[String],mane_select:String,mane_plus_clinical:String,mirna:Array[String],polyphen_prediction:String,polyphen_score:Float64,protein_end:Int32,protein_id:String,protein_start:Int32,sift_prediction:String,sift_score:Float64,source:String,strand:Int32,swissprot:Array[String],transcript_id:String,trembl:Array[String],tsl:Int32,uniparc:Array[String],uniprot_isoform:Array[String],used_ref:String,variant_allele:String}],variant_class:String}"
 }
 EOF