Fix #4906 - warn on potentially conflicting ACMG terms.

CHANGELOG.md

@@ -9,6 +9,7 @@ About changelog [here](https://keepachangelog.com/en/1.0.0/)
 - Link to chanjo2 MANE coverage overview on case page and panel page
 - More SVI recommendation links on the ACMG page
 - IGV buttons for SMN CN page
+- Warnings on ACMG classifications for potentially conflicting classification pairs
 ### Changed
 - Variants query backend allows rank_score filtering
 - Added script to tabulate causatives clinical filter rank

scout/constants/acmg.py

@@ -297,7 +297,7 @@
                     (
                         "BP7",
                         {
-                            "short": "(not in use)",
+                            "short": "Synonymous, no splice impact",
                             "description": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site",
                         },
                     ),
@@ -306,3 +306,51 @@
         ),
     ]
 )
+
+ACMG_POTENTIAL_CONFLICTS = [
+    (
+        "PVS1",
+        "PM4",
+        "Use of PVS1 and PM4 together risks double-counting evidence (Tayoun et al 2019).",
+    ),
+    (
+        "PVS1",
+        "PM1",
+        "Use of PVS1 and PM1 together is not recommended (Durkie et al 2024).",
+    ),
+    (
+        "PVS1",
+        "PP2",
+        "Use of PVS1 and PP2 together is not recommended (Durkie et al 2024).",
+    ),
+    (
+        "PVS1",
+        "PS3",
+        "Note that for RNA PS3 should only be taken with PVS1 for well established functional assays, not splicing alone (Walker 2023).",
+    ),
+    (
+        "PS1",
+        "PM4",
+        "Use of PS1 and PM4 together is not recommended (Durkie et al 2024).",
+    ),
+    (
+        "PS1",
+        "PM5",
+        "Use of PS1 and PM5 together conflicts with original definition (Richards et al 2015).",
+    ),
+    (
+        "PS1",
+        "PP3",
+        "Use of PS1 and PP3 together risks double-counting evidence (Tayoun et al 2019).",
+    ),
+    (
+        "PS2",
+        "PM6",
+        "Use of PS2 and PM6 together conflicts with original definition (Richards et al 2015).",
+    ),
+    (
+        "PM1",
+        "PP2",
+        "Avoid double-counting evidence for constraints in both PM1 and PP2 (Durkie et al 2024).",
+    ),
+]

scout/server/blueprints/variant/templates/variant/acmg.html

@@ -42,14 +42,7 @@ <h4>
           {% elif not evaluation %}
             <button class="btn btn-primary form-control">Submit</button>
           {% endif %}
-          <!-- classification preview in the footer-->
-          <div class="mt-3 fixed-bottom bg-light border">
-              <div class="text-center">
-                {% for option in ACMG_OPTIONS %}
-                  <a id="acmg-{{ option.code }}" class="btn acmg-preview">{{ option.label }}</a>
-                {% endfor %}
-              </div>
-          </div>
+          <div id="conflicts_div" class="bg-warning"></div>
         </div>
       </div>
 
@@ -108,6 +101,14 @@ <h4>Evidence of {{ category }}</h4>
           </div>
         {% endfor %}
       </div>
+    <!-- classification preview in the footer-->
+      <div class="mt-3 fixed-bottom bg-light border">
+        <div class="text-center">
+          {% for option in ACMG_OPTIONS %}
+            <a id="acmg-{{ option.code }}" class="btn acmg-preview">{{ option.label }}</a>
+          {% endfor %}
+        </div>
+      </div>
     </form>
   </div>
 {% endblock %}
@@ -166,12 +167,16 @@ <h5>Likely Pathogenic</h5>
         return 'criterion=' + elem.value
       });
 
-
       $.getJSON('/api/v1/acmg?' + criteria.toArray().join('&'), function(data) {
         // reset the selection
         $('.acmg-preview').removeClass('btn-primary');
         // add new selection
         $('#acmg-' + data.classification).addClass('btn-primary');
+
+        // Update any classification conflicts
+        var conflicts_div = document.getElementById("conflicts_div");
+        conflicts_div.innerHTML = data.conflicts.join("<br>");
+
       });
     }
   </script>

scout/server/blueprints/variant/views.py

@@ -26,7 +26,7 @@
 )
 from scout.server.extensions import loqusdb, store
 from scout.server.utils import institute_and_case, public_endpoint, templated
-from scout.utils.acmg import get_acmg
+from scout.utils.acmg import get_acmg, get_acmg_conflicts
 from scout.utils.ensembl_rest_clients import EnsemblRestApiClient
 
 LOG = logging.getLogger(__name__)
@@ -347,7 +347,8 @@ def acmg():
     """Calculate an ACMG classification from submitted criteria."""
     criteria = request.args.getlist("criterion")
     classification = get_acmg(criteria)
-    return jsonify(dict(classification=classification))
+    acmg_conflicts = get_acmg_conflicts(criteria)
+    return jsonify({"classification": classification, "conflicts": acmg_conflicts})
 
 
 @variant_bp.route(

scout/utils/acmg.py

@@ -1,4 +1,9 @@
 # coding=UTF-8
+from flask import flash
+
+from scout.constants.acmg import ACMG_POTENTIAL_CONFLICTS
+
+
 def is_pathogenic(pvs, ps_terms, pm_terms, pp_terms):
     """Check if the criterias for Pathogenic is fullfilled
 
@@ -249,3 +254,14 @@ def get_acmg(acmg_terms):
             prediction = "likely_benign"
 
     return prediction
+
+
+def get_acmg_conflicts(acmg_terms: set) -> list:
+    """Check potential conflict paris, return list of reference strings."""
+
+    conflicts = []
+    for t1, t2, reference in ACMG_POTENTIAL_CONFLICTS:
+        if t1 in acmg_terms and t2 in acmg_terms:
+            conflicts.append(reference)
+
+    return conflicts

tests/utils/test_acmg.py

@@ -1,5 +1,6 @@
 from scout.utils.acmg import (
     get_acmg,
+    get_acmg_conflicts,
     is_benign,
     is_likely_benign,
     is_likely_pathogenic,
@@ -433,3 +434,9 @@ def test_acmg_benign_moderate():
     acmg_terms = {"BP1_Moderate", "BS1"}
     res = get_acmg(acmg_terms)
     assert res == "likely_benign"
+
+
+def test_acmg_conflicts():
+    acmg_terms = {"PVS1", "PM4"}
+    conflicts = get_acmg_conflicts(acmg_terms)
+    assert len(conflicts) == 1