{ "name": "WGS rare disease proband profile", "profileUid": "wgs_rare_disease_proband_v1", "version": "1.0", "visibility": "community", "domain": "clinical_genetics", "standard": "SGA-QEM-1.0", "standardVersion": "1.0", "description": "Public evidence profile for rare disease whole genome sequencing review in QuantBayes Studio.", "scope": "Single proband WGS candidate variant review where evidence is assessed across genotype validity, population frequency, public clinical assertions, gene disease consistency, phenotype fit, control observations, and UniProt functional annotation.", "maintainer": "Swiss Genomics Association", "sourceUrl": "", "rules": [ { "ruleOrder": 1, "ruleUid": "proband_genotype_invalid", "name": "Proband genotype invalid", "description": "Is the proband genotype missing, invalid, failed, or not reliably interpretable?", "evidenceMeaning": "The proband genotype is present, interpretable, and inspectable in the source data.", "problemMeaning": "The proband genotype is missing, invalid, failed, or cannot be interpreted reliably.", "notAvailableMeaning": "Proband genotype evidence is unavailable or cannot be assessed." }, { "ruleOrder": 2, "ruleUid": "population_frequency_common", "name": "Population frequency common", "description": "Is the population allele frequency too common for a rare disease model?", "evidenceMeaning": "Population frequency evidence is available and remains below the configured rare disease threshold.", "problemMeaning": "Population frequency is too high, exceeds the configured threshold, or is incompatible with a rare disease model.", "notAvailableMeaning": "Population frequency compatibility cannot be assessed." }, { "ruleOrder": 3, "ruleUid": "population_frequency_unavailable", "name": "Population frequency unavailable", "description": "Is population allele frequency information unavailable for this variant?", "evidenceMeaning": "Population allele frequency evidence is available from a traceable reference source.", "problemMeaning": "Population allele frequency evidence is missing, unavailable, or not traceable.", "notAvailableMeaning": "Population frequency availability is unknown or cannot be assessed." }, { "ruleOrder": 4, "ruleUid": "gnomad_flag_present", "name": "gnomAD flag present", "description": "Is at least one gnomAD warning flag present for this variant?", "evidenceMeaning": "No gnomAD warning flags are present and the population annotation is inspectable.", "problemMeaning": "At least one gnomAD warning flag is present or the annotation has a flagged problem.", "notAvailableMeaning": "gnomAD flag status is unavailable or cannot be assessed." }, { "ruleOrder": 5, "ruleUid": "acmg_benign_evidence_present", "name": "ACMG benign evidence present", "description": "Is ACMG benign evidence present for this variant?", "evidenceMeaning": "No ACMG benign evidence is present in the available annotation.", "problemMeaning": "ACMG benign evidence is present, suggesting the variant may be harmless.", "notAvailableMeaning": "ACMG evidence is unavailable or cannot be assessed." }, { "ruleOrder": 6, "ruleUid": "clinvar_benign_conflict", "name": "ClinVar benign conflict", "description": "Is benign or conflicting ClinVar evidence present?", "evidenceMeaning": "ClinVar evidence is available and no benign or conflicting interpretation is present.", "problemMeaning": "ClinVar contains benign, likely benign, conflicting, or otherwise contradictory interpretation evidence.", "notAvailableMeaning": "ClinVar evidence is unavailable or cannot be assessed." }, { "ruleOrder": 7, "ruleUid": "genedisease_validity_weak", "name": "Gene disease validity weak", "description": "Is gene disease validity weak, missing, insufficient, or not traceable?", "evidenceMeaning": "Gene disease validity is present, traceable, and sufficient for the interpretation context.", "problemMeaning": "Gene disease validity is weak, missing, insufficient, or not traceable.", "notAvailableMeaning": "Gene disease validity evidence is unavailable or cannot be assessed." }, { "ruleOrder": 8, "ruleUid": "omim_inconsistency", "name": "OMIM inconsistency", "description": "Is OMIM evidence missing, contradictory, or inconsistent with the gene or inheritance context?", "evidenceMeaning": "OMIM evidence is present and compatible with the gene, disease, and inheritance context.", "problemMeaning": "OMIM evidence is missing, contradictory, or inconsistent with the gene or inheritance context.", "notAvailableMeaning": "OMIM evidence is unavailable or cannot be assessed." }, { "ruleOrder": 9, "ruleUid": "lof_mechanism_inconsistent", "name": "Loss of function mechanism inconsistent", "description": "Is the proposed loss of function mechanism inconsistent with known gene biology?", "evidenceMeaning": "Loss of function mechanism evidence is present and compatible with known gene biology.", "problemMeaning": "Loss of function mechanism evidence is inconsistent, unsupported, missing, or contradictory.", "notAvailableMeaning": "Loss of function mechanism evidence is unavailable, unmeasured, or not applicable." }, { "ruleOrder": 10, "ruleUid": "phenotype_mismatch", "name": "Phenotype mismatch", "description": "Is the patient phenotype insufficiently compatible with the gene or disease model?", "evidenceMeaning": "Phenotype evidence is available and sufficiently compatible with the gene or disease model.", "problemMeaning": "Phenotype evidence is missing, insufficient, below threshold, or incompatible with the gene or disease model.", "notAvailableMeaning": "Phenotype evidence is unavailable or cannot be assessed." }, { "ruleOrder": 11, "ruleUid": "disease_spectrum_mismatch", "name": "Disease spectrum mismatch", "description": "Is the clinical presentation incompatible with the known disease spectrum?", "evidenceMeaning": "Disease spectrum evidence is available and compatible with the clinical presentation.", "problemMeaning": "Disease spectrum evidence is missing, insufficient, contradictory, or incompatible with the clinical presentation.", "notAvailableMeaning": "Disease spectrum evidence is unavailable or cannot be assessed." }, { "ruleOrder": 12, "ruleUid": "present_in_controls", "name": "Present in controls", "description": "Is the variant present in unaffected control observations?", "evidenceMeaning": "Control evidence is available and the variant is absent from relevant unaffected controls.", "problemMeaning": "The variant is present in controls, control evidence conflicts with pathogenicity, or control review failed.", "notAvailableMeaning": "Control evidence is unavailable or cannot be assessed." }, { "ruleOrder": 13, "ruleUid": "flag_uniprot_no_feature_overlap", "name": "No UniProt feature overlap", "description": "Does the variant lack overlap with a UniProt annotated feature?", "evidenceMeaning": "The variant overlaps a UniProt annotated feature and functional annotation evidence is available.", "problemMeaning": "The variant lacks UniProt feature overlap, so functional annotation evidence is absent.", "notAvailableMeaning": "UniProt feature annotation is unavailable or cannot be assessed." }, { "ruleOrder": 14, "ruleUid": "flag_uniprot_no_domain_overlap", "name": "No UniProt domain overlap", "description": "Does the variant lack overlap with a UniProt domain-like region?", "evidenceMeaning": "The variant overlaps a UniProt domain-like region and domain evidence is available.", "problemMeaning": "The variant lacks UniProt domain overlap, so domain evidence is absent.", "notAvailableMeaning": "UniProt domain annotation is unavailable or cannot be assessed." }, { "ruleOrder": 15, "ruleUid": "flag_uniprot_no_structural_overlap", "name": "No UniProt structural overlap", "description": "Does the variant lack overlap with a UniProt structural element?", "evidenceMeaning": "The variant overlaps a UniProt structural element and structural evidence is available.", "problemMeaning": "The variant lacks UniProt structural overlap, so structural evidence is absent.", "notAvailableMeaning": "UniProt structural annotation is unavailable or cannot be assessed." }, { "ruleOrder": 16, "ruleUid": "flag_uniprot_no_ptm_overlap", "name": "No UniProt PTM overlap", "description": "Does the variant lack overlap with a UniProt post-translational modification region?", "evidenceMeaning": "The variant overlaps a UniProt post-translational modification region and PTM evidence is available.", "problemMeaning": "The variant lacks UniProt PTM overlap, so PTM evidence is absent.", "notAvailableMeaning": "UniProt PTM annotation is unavailable or cannot be assessed." }, { "ruleOrder": 17, "ruleUid": "flag_uniprot_no_binding_overlap", "name": "No UniProt binding overlap", "description": "Does the variant lack overlap with a UniProt binding or active site region?", "evidenceMeaning": "The variant overlaps a UniProt binding or active site region and interaction evidence is available.", "problemMeaning": "The variant lacks UniProt binding or active site overlap, so interaction evidence is absent.", "notAvailableMeaning": "UniProt binding annotation is unavailable or cannot be assessed." }, { "ruleOrder": 18, "ruleUid": "flag_uniprot_no_variant_site_overlap", "name": "No UniProt variant site overlap", "description": "Does the variant lack overlap with a UniProt variant or mutagenesis site?", "evidenceMeaning": "The variant overlaps a UniProt variant or mutagenesis site and experimental annotation evidence is available.", "problemMeaning": "The variant lacks UniProt variant or mutagenesis site overlap, so experimental evidence is absent.", "notAvailableMeaning": "UniProt experimental annotation is unavailable or cannot be assessed." }, { "ruleOrder": 19, "ruleUid": "flag_uniprot_not_lof", "name": "Not loss of function", "description": "Is the variant not predicted to be loss of function where loss of function evidence is required?", "evidenceMeaning": "The variant has a loss of function consequence and LoF mechanism evidence is available.", "problemMeaning": "The variant is not predicted loss of function, so LoF mechanism evidence is absent.", "notAvailableMeaning": "Variant consequence evidence is unavailable, unmeasured, or not applicable." }, { "ruleOrder": 20, "ruleUid": "flag_uniprot_nmd_not_predicted", "name": "NMD not predicted", "description": "Is nonsense-mediated decay not predicted where transcript loss of function evidence is required?", "evidenceMeaning": "Nonsense-mediated decay is predicted and transcript loss of function evidence is available.", "problemMeaning": "Nonsense-mediated decay is not predicted, so transcript loss of function evidence is absent.", "notAvailableMeaning": "NMD prediction evidence is unavailable, unmeasured, or not applicable." }, { "ruleOrder": 21, "ruleUid": "flag_uniprot_no_feature_truncation", "name": "No UniProt feature truncation", "description": "Does the variant fail to truncate a downstream UniProt annotated feature?", "evidenceMeaning": "The variant truncates a downstream UniProt annotated feature and truncation evidence is available.", "problemMeaning": "The variant does not truncate a downstream UniProt annotated feature, so truncation evidence is absent.", "notAvailableMeaning": "UniProt truncation annotation is unavailable or cannot be assessed." } ] }