Update version to 13.1.0

docs/acmg_assignment.rst

@@ -0,0 +1,245 @@
+.. _acmg_assignment:
+
+===============
+ACMG Assignment
+===============
+
+Starting with version 13.1.0, Exomiser performs a partial categorisation of the variants contributing to the gene
+score for a mode of inheritance using the ACMG/AMP `Standards and guidelines for the interpretation of sequence
+variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association
+for Molecular Pathology <https://doi.org/10.1038/gim.2015.30>`_. The criteria are assigned and combined according to the
+`UK ACGS 2020 guidelines <https://www.acgs.uk.com/media/11631/uk-practice-guidelines-for-variant-classification-v4-01-2020.pdf>`_.
+
+It is important to be aware that these scores are not a substitute for manual assignment by a qualified clinical geneticist
+or clinician - The scores displayed utilise the data found in the Exomiser database and are a subset of the possible
+criteria by which to assess a variant. Nonetheless, in our benchmarking on the returned cases from the 100K Genomes Project,
+restricting to variants with these automated P/LP classifications increases precision (positive predictive value) markedly
+without excluding many real diagnoses. For example, on a cohort of 742 solved cases where the top 5 Exomiser candidates
+were considered, including the P/LP criteria increased precision 3.8-fold from 15% to 57% with only a small drop in the
+recall of the diagnoses from 94% to 83%. An even larger 5.7-fold increase of precision from 3% to 17% was observed when
+considering a larger cohort of 31k cases where only 17% had received a positive diagnosis (again with a modest drop in
+recall from 91% to 75%).
+
+Exomiser is capable of assigning the following ACMG categories:
+
+Computational and Predictive Data
+=================================
+PVS1
+----
+Variants must have a predicted loss of function effect, be in a gene with known disease associations and have a gene
+constraint LOF O/E < 0.7635 (gnomAD 2.1.1) to suggest that a gene is LoF intolerant. Variants not predicted to lead to
+NMD (those located in the last exon) will have the modifier downgraded to Strong.
+
+PM4
+---
+Stop-loss and in-frame insertions or deletions, not previously assigned a `PVS1` criterion are assigned `PM4`.
+
+PP3 / BP4
+---------
+If REVEL is chosen as a pathogenicity predictor for missense variants, `PP3` and `BP4` are assigned using the modifiers
+according to table 2 of `Evidence-based calibration of computational tools for missense variant pathogenicity classification
+and ClinGen recommendations for clinical use of PP3/BP4 criteria <https://www.biorxiv.org/content/10.1101/2022.03.17.484479v1>`_.
+Note that this suggests the use of modifiers up to Strong in the case of pathogenic or Very Strong in the case of benign predictions.
+Otherwise, an ensemble-based approach will be used for other pathogenicity predictors as per the original 215 guidelines.
+It should be noted we found better performance using the REVEL-based approach when testing against the 100K genomes data.
+
+Segregation Data
+================
+BS4
+---
+If a pedigree with two or more members, including the proband is provided, Exomiser will assign `BS4` for variants not
+segregating with affected members of the family.
+
+De novo Data
+===========
+
+PS2
+---
+Exomiser assigns the `PS2` criterion for variants compatible with a dominant mode of inheritance, with a pedigree containing
+at least two ancestors of the proband, none of whom are affected and none of whom share the same allele as the proband.
+
+Population Data
+===============
+BA1
+---
+Given Exomiser will filter out alleles with an allele frequency of >= 2.0%, this is unlikely to be seen. However, alleles
+with a maximum frequency >= 5.0% in the frequency sources specified will be assigned the `BA1` criterion.
+
+PM2
+---
+Alleles not present in the ESP, ExAC and 1000 Genomes data sets (i.e. the allele must be absent from all three) are
+assigned the `PM2` criterion.
+
+Allelic Data
+============
+PM3 / BP2
+---------
+If Exomiser is provided with a phased VCF and a variant is found to be *in-trans* with a ClinVar Pathogenic variant and
+associated with a recessive disorder, the `PM3` criterion will be applied. However, in cases where variant is being
+considered for a recessive disorder and is *in-cis* or a dominant disorder and *in-trans* with another pathogenic variant
+the `BP2` criterion is applied.
+
+
+Phenotype
+=========
+PP4
+---
+Given Exomiser's focus on phenotype-driven variant prioritisation, variants in a gene associated with a disorder with a
+phenotype match score > 0.6 to the patient's phenotype are assigned the `PP4` criterion at the Moderate, rather than
+Supporting level.
+
+Clinical
+========
+PP5 / BP6
+--------
+If a variant is previously reported as P/LP in ClinVar with a 1-start rating, it will be assigned `PP5`, those with >= 2
+stars (multiple submitters, criteria provided, no conflicts / reviewed by expert panel / practice guideline) will be
+assigned a Strong level. Conversely, if the variant is previously reported as B/LB it will be assigned `BP6` with the same
+modification criteria. Typically these P/LP variants will be in the Exomiser ClinVar 'whitelist', and will have
+a very high variant score irrespective of the predicted variant effect and always survive any filtering criteria.
+
+
+Transcript Selection
+====================
+
+Transcripts will be selected using the most deleterious predicted variant effect from `Jannovar <https://doi.org/10.1002/humu.22531>`_
+according to the `transcript-source` property set in the `application.properties`. We recommend using the Ensembl
+transcript datasource as the Exomiser build uses the GENCODE basic set of transcripts. Future versions should use MANE transcripts.
+
+ACMG assignments will be reported for a variant on a transcript consistent with a particular mode of inheritance in
+conjunction with a disorder, the assigned criteria with any modifiers and the final classification e.g.
+
+.. parsed-literal::
+
+   1-12335-A-T, NC_000001.10:g.12335A>T, GENE1(ENST12345678):c.2346A>T:p.1234A>-, PATHOGENIC, [PVS1, PS1, PP4_Strong], Disease (OMIM:12345), AUTOSOMAL_DOMINANT
+
+
+.. code-block:: json
+
+        "acmgAssignments": [
+          {
+            "variantEvaluation": {
+              "genomeAssembly": "HG19",
+              "contigName": "10",
+              "start": 123256215,
+              "end": 123256215,
+              "ref": "T",
+              "alt": "G",
+              "type": "SNV",
+              "length": 1,
+              "phredScore": 100,
+              "variantEffect": "MISSENSE_VARIANT",
+              "whiteListed": true,
+              "filterStatus": "PASSED",
+              "contributesToGeneScore": true,
+              "variantScore": 1,
+              "frequencyScore": 1,
+              "pathogenicityScore": 1,
+              "predictedPathogenic": true,
+              "passedFilterTypes": [
+                "FAILED_VARIANT_FILTER",
+                "PATHOGENICITY_FILTER",
+                "FREQUENCY_FILTER",
+                "VARIANT_EFFECT_FILTER",
+                "INHERITANCE_FILTER"
+              ],
+              "frequencyData": {
+                "rsId": "rs121918506",
+                "score": 1
+              },
+              "pathogenicityData": {
+                "clinVarData": {
+                  "alleleId": "28333",
+                  "primaryInterpretation": "LIKELY_PATHOGENIC",
+                  "reviewStatus": "criteria provided, single submitter"
+                },
+                "score": 0.965,
+                "predictedPathogenicityScores": [
+                  {
+                    "source": "REVEL",
+                    "score": 0.965
+                  },
+                  {
+                    "source": "MVP",
+                    "score": 0.9517972
+                  }
+                ],
+                "mostPathogenicScore": {
+                  "source": "REVEL",
+                  "score": 0.965
+                }
+              },
+              "compatibleInheritanceModes": [
+                "AUTOSOMAL_DOMINANT"
+              ],
+              "contributingInheritanceModes": [
+                "AUTOSOMAL_DOMINANT"
+              ],
+              "transcriptAnnotations": [
+                {
+                  "variantEffect": "MISSENSE_VARIANT",
+                  "geneSymbol": "FGFR2",
+                  "accession": "ENST00000346997.2",
+                  "hgvsGenomic": "g.12278533A>C",
+                  "hgvsCdna": "c.1688A>C",
+                  "hgvsProtein": "p.(Glu563Ala)",
+                  "rankType": "EXON",
+                  "rank": 12,
+                  "rankTotal": 17
+                },
+                {
+                  "variantEffect": "MISSENSE_VARIANT",
+                  "geneSymbol": "FGFR2",
+                  "accession": "ENST00000351936.6",
+                  "hgvsGenomic": "g.12278533A>C",
+                  "hgvsCdna": "c.1688A>C",
+                  "hgvsProtein": "p.(Glu563Ala)",
+                  "rankType": "EXON",
+                  "rank": 13,
+                  "rankTotal": 18
+                }
+              ]
+            },
+            "geneIdentifier": {
+              "geneId": "ENSG00000066468",
+              "geneSymbol": "FGFR2",
+              "hgncId": "HGNC:3689",
+              "hgncSymbol": "FGFR2",
+              "entrezId": "2263",
+              "ensemblId": "ENSG00000066468",
+              "ucscId": "uc057wle.1"
+            },
+            "modeOfInheritance": "AUTOSOMAL_DOMINANT",
+            "disease": {
+              "diseaseId": "OMIM:123150",
+              "diseaseName": "Jackson-Weiss syndrome",
+              "associatedGeneId": 2263,
+              "diseaseType": "DISEASE",
+              "inheritanceMode": "AUTOSOMAL_DOMINANT",
+              "phenotypeIds": [
+                "HP:0000006",
+                "HP:0000272",
+                "HP:0001363",
+                "HP:0001783",
+                "HP:0004691",
+                "HP:0008080",
+                "HP:0008122",
+                "HP:0010055",
+                "HP:0010743",
+                "HP:0011800"
+              ],
+              "id": "OMIM:123150",
+              "associatedGeneSymbol": "FGFR2"
+            },
+            "acmgEvidence": {
+              "evidence": {
+                "PM2": "MODERATE",
+                "PP3": "STRONG",
+                "PP4": "SUPPORTING",
+                "PP5": "SUPPORTING"
+              }
+            },
+            "acmgClassification": "LIKELY_PATHOGENIC"
+          }
+        ]
+      }