Poc/alphamissense

config/nxf_vcf.config

@@ -73,6 +73,7 @@ params {
         vep_plugin_utrannotator = "${projectDir}/resources/GRCh38/uORF_5UTR_PUBLIC.txt"
         vep_plugin_vkgl = "${projectDir}/resources/GRCh38/vkgl_consensus_20231101.tsv"
         vep_plugin_alphscore = "${projectDir}/resources/GRCh38/AlphScore_final_20230825_stripped_GRCh38.tsv.gz"
+        vep_plugin_alphaMissense = "${projectDir}/_dev/resources/AlphaMissense_hg38.tsv.gz"
         vep_plugin_ncer = "${projectDir}/resources/GRCh38/GRCh38_ncER_perc.bed.gz"
       }
     }
@@ -98,7 +99,7 @@ params {
     }
 
     filter {
-      classes = "VUS,LP,P"
+      classes = "VUS,LP,P,LP_AM"
       consequences = true
     }
 

install.sh

@@ -134,6 +134,8 @@ download_files() {
   urls+=("9aea133bbe8dea635172e6de0cf05edf" "resources/hpo_20230822.tsv")
   urls+=("df31eb0fe9ebd9ae26c8d6f5f7ba6e57" "resources/inheritance_20240115.tsv")
   urls+=("7138e76a38d6f67935699d06082ecacf" "resources/vep/cache/homo_sapiens_refseq_vep_111_GRCh38.tar.gz")
+  urls+=("9fd167735f16a1b87da6eb3e4c25fcb5" "_dev/resources/AlphaMissense_hg38.tsv.gz")
+  urls+=("d2b23d618660cb2a7acfba17170dfd4c" "_dev/resources/AlphaMissense_hg38.tsv.gz.tbi")
   # when modifying urls array, please keep list in 'ls -l' order
 
   for ((i = 0; i < ${#urls[@]}; i += 2)); do

modules/vcf/annotate.nf

@@ -29,6 +29,7 @@ process annotate {
     vepPluginNcerPath = params.vcf.annotate[assembly].vep_plugin_ncer
     capiceModelPath = params.vcf.annotate[assembly].capice_model
     alphScorePath = params.vcf.annotate[assembly].vep_plugin_alphscore
+    alphaMissensePath = params.vcf.annotate[assembly].vep_plugin_alphaMissense
     strangerCatalog = params.vcf.annotate[assembly].stranger_catalog
 
     areProbandHpoIdsIndentical = areProbandHpoIdsIndentical(meta.project.samples)

modules/vcf/templates/annotate.sh

@@ -185,6 +185,10 @@ vep() {
   if [ -n "!{alphScorePath}" ]; then
     args+=("--plugin" "AlphScore,!{alphScorePath}")
   fi
+  if [ -n "!{alphaMissensePath}" ]; then
+    #The plugin supports transcript matching, but we this wont work for us due to it being based on ensembl id's
+    args+=("--plugin" "AlphaMissense,file=!{alphaMissensePath},cols=all")
+  fi
   if [ -n "!{vepPluginNcerPath}" ]; then
     args+=("--plugin" "ncER,!{vepPluginNcerPath}")
   fi

resources/decision_tree_GRCh38.json

@@ -395,11 +395,29 @@
         "nextNode": "exit_lp"
       },
       "outcomeFalse": {
-        "nextNode": "exit_lb"
+        "nextNode": "alphaMissense"
       },
       "outcomeMissing": {
         "nextNode": "exit_vus"
       }
+    },    
+    "alphaMissense": {
+      "description": "AlphaMissense pathogenicity score > 0.2977",
+      "type": "BOOL",
+      "query": {
+        "field": "INFO/CSQ/am_pathogenicity",
+        "operator": ">",
+        "value": 0.2977
+      },
+      "outcomeTrue": {
+        "nextNode": "exit_lp_am"
+      },
+      "outcomeFalse": {
+        "nextNode": "exit_lb_am"
+      },
+      "outcomeMissing": {
+        "nextNode": "exit_lb"
+      }
     },
     "exit_rm": {
       "description": "Remove",
@@ -411,6 +429,11 @@
       "type": "LEAF",
       "class": "B"
     },
+    "exit_lb_am": {
+      "description": "Benign (Alpha Missense)",
+      "type": "LEAF",
+      "class": "LB_AM"
+    },
     "exit_lb": {
       "description": "Likely Benign",
       "type": "LEAF",
@@ -426,6 +449,11 @@
       "type": "LEAF",
       "class": "LP"
     },
+    "exit_lp_am": {
+      "description": "Likely Pathogenic (AlphaMissense)",
+      "type": "LEAF",
+      "class": "LP_AM"
+    },
     "exit_p": {
       "description": "Pathogenic",
       "type": "LEAF",

resources/field_metadata.json

@@ -34,6 +34,13 @@
           "numberType": "NUMBER",
           "numberCount": 1,
           "type": "FLOAT"
+        },
+         "am_pathogenicity": {
+          "label": "AlphaMissense Score",
+          "description": "AlphaMissense pathogenicity score for missense variants",
+          "numberType": "NUMBER",
+          "numberCount": 1,
+          "type": "FLOAT"
         },
         "CAPICE_CL": {
           "label": "CAPICE",