{ "data": { "@context": "https://genboree.org/evrepo/api/context", "@id": "https://genboree.org/evrepo/api/summary/classification/c2cf447a-486b-46db-9aec-0c3e8f56633d/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1564418400", "label": "ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ADA Version 1.0.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "1.0.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0007064", "id": "MONDO:0007064", "label": "adenosine deaminase deficiency", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://genboree.org/evrepo/api/interpretation/CA9871496/MONDO:0007064/114/el/0/1636", "evidenceItem": [ { "@id": "https://genboree.org/evrepo/api/interpretation/CA9871496/MONDO:0007064/114/ei/1/1637", "contribution": [ { "agent": { "@id": "https://genboree.org/evrepo/api//agent/CG_50091_EP170474609917003", "id": "CG-PCER-AGENT:CG_50091_EP170474609917003", "type": "Agent" }, "contributionDate": { "date": "2024/1/23", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0030", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0030", "label": "PM2", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://genboree.org/evrepo/api/interpretation/CA9871496/MONDO:0007064/114/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA9871496/MONDO:0007064/114/ci/CA9871496/MONDO:0007064/114.002", "contribution": [ { "agent": { "@id": "https://genboree.org/evrepo/api//agent/CG_50091_EP170474609917003", "id": "CG-PCER-AGENT:CG_50091_EP170474609917003", "type": "Agent" }, "comments": "The highest population minor allele frequency in gnomAD v4 is 0.000005310 (12/1180048 alleles) in \nEuropean (non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, meeting this criterion (PM2_Supporting). ", "contributionDate": { "date": "2024/1/23", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA9871496/MONDO:0007064/114/ci/CA9871496/MONDO:0007064/114.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA9871496/MONDO:0007064/114/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA9871496/MONDO:0007064/114/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA9871496/MONDO:0007064/114/0/1636", "type": "EvidenceLine" }, { "@id": "https://genboree.org/evrepo/api/interpretation/CA9871496/MONDO:0007064/114/el/0/1651", "evidenceItem": [ { "@id": "https://genboree.org/evrepo/api/interpretation/CA9871496/MONDO:0007064/114/ei/1/1652", "contribution": [ { "agent": { "@id": "https://genboree.org/evrepo/api//agent/CG_50091_EP170474609917003", "id": "CG-PCER-AGENT:CG_50091_EP170474609917003", "type": "Agent" }, "contributionDate": { "date": "2024/1/23", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0058", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000330", "id": "SEPIO:0000330", "label": "Pathogenic Strong" }, "id": "0058", "label": "PM3", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://genboree.org/evrepo/api/interpretation/CA9871496/MONDO:0007064/114/el/0/1651/1653", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA9871496/MONDO:0007064/114/ci/CA9871496/MONDO:0007064/114.002", "contribution": [ { "agent": { "@id": "https://genboree.org/evrepo/api//agent/CG_50091_EP170474609917003", "id": "CG-PCER-AGENT:CG_50091_EP170474609917003", "type": "Agent" }, "comments": "PMID: 32307643, Patients 3 and 25, both are homozygous, reaching the maximum of 1 point for homozygous occurrence. From the same report, patient 2: Compound heterozygous,c.221G>T, p.G74V, Likely Pathogenic according to SCID VCEP specifications; 1 point. Total 2 points, PM3_Strong.\t", "contributionDate": { "date": "2024/1/23", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA9871496/MONDO:0007064/114/ci/CA9871496/MONDO:0007064/114.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA9871496/MONDO:0007064/114/0/1651/1653", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA9871496/MONDO:0007064/114/1/1652", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA9871496/MONDO:0007064/114/0/1651", "type": "EvidenceLine" }, { "@id": "https://genboree.org/evrepo/api/interpretation/CA9871496/MONDO:0007064/114/el/0/1762", "evidenceItem": [ { "@id": "https://genboree.org/evrepo/api/interpretation/CA9871496/MONDO:0007064/114/ei/1/1763", "contribution": [ { "agent": { "@id": "https://genboree.org/evrepo/api//agent/CG_50091_EP170474609917003", "id": "CG-PCER-AGENT:CG_50091_EP170474609917003", "type": "Agent" }, "contributionDate": { "date": "2024/1/23", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0020", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000330", "id": "SEPIO:0000330", "label": "Pathogenic Strong" }, "id": "0020", "label": "PVS1", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://genboree.org/evrepo/api/interpretation/CA9871496/MONDO:0007064/114/el/0/1762/1764", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA9871496/MONDO:0007064/114/ci/CA9871496/MONDO:0007064/114.002", "contribution": [ { "agent": { "@id": "https://genboree.org/evrepo/api//agent/CG_50091_EP170474609917003", "id": "CG-PCER-AGENT:CG_50091_EP170474609917003", "type": "Agent" }, "comments": "The c.845G>A (p.Arg282Gln) variant is considered in the PVS1 criteria based on experimental evidence indicating that it has the effect of affecting the splicing site. In line with the predictions of splicing algorithms, experimental validation (from Dr. Mike Hershfield - Internal Communication) has established that the variant occurs at the splice junction between exon 9 and intron 10 and has been shown to cause aberrant splicing in peripheral blood leukocytes (PBL) of a female Arab patient with ADA-SCID.\nBased on this, we classify PVS1 at a Strong level, as it results in the loss of more than 10% of the protein, and other pathogenic variants have already been described downstream (e.g., NM_000022.4(ADA):c.870C>A (p.Tyr290Ter), Pathogenic according to SCID VCEP specifications).", "contributionDate": { "date": "2024/1/23", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA9871496/MONDO:0007064/114/ci/CA9871496/MONDO:0007064/114.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA9871496/MONDO:0007064/114/0/1762/1764", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA9871496/MONDO:0007064/114/1/1763", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA9871496/MONDO:0007064/114/0/1762", "type": "EvidenceLine" }, { "@id": "https://genboree.org/evrepo/api/interpretation/CA9871496/MONDO:0007064/114/el/0/1780", "evidenceItem": [ { "@id": "https://genboree.org/evrepo/api/interpretation/CA9871496/MONDO:0007064/114/ei/1/1781", "contribution": [ { "agent": { "@id": "https://genboree.org/evrepo/api//agent/CG_50091_EP170474609917003", "id": "CG-PCER-AGENT:CG_50091_EP170474609917003", "type": "Agent" }, "contributionDate": { "date": "2024/1/23", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/008", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000216", "id": "SEPIO:0000216", "label": "Pathogenic Moderate" }, "id": "008", "label": "PM5", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://genboree.org/evrepo/api/interpretation/CA9871496/MONDO:0007064/114/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA9871496/MONDO:0007064/114/ci/CA9871496/MONDO:0007064/114.002", "contribution": [ { "agent": { "@id": "https://genboree.org/evrepo/api//agent/CG_50091_EP170474609917003", "id": "CG-PCER-AGENT:CG_50091_EP170474609917003", "type": "Agent" }, "comments": "NM_000022.4(ADA):c.844C>T (p.Arg282Trp) is VUS according to SCID VCEP specifications, and PM5 is not met.", "contributionDate": { "date": "2024/1/23", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA9871496/MONDO:0007064/114/ci/CA9871496/MONDO:0007064/114.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA9871496/MONDO:0007064/114/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA9871496/MONDO:0007064/114/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA9871496/MONDO:0007064/114/0/1780", "type": "EvidenceLine" }, { "@id": "https://genboree.org/evrepo/api/interpretation/CA9871496/MONDO:0007064/114/el/0/1831", "evidenceItem": [ { "@id": "https://genboree.org/evrepo/api/interpretation/CA9871496/MONDO:0007064/114/ei/1/1832", "contribution": [ { "agent": { "@id": "https://genboree.org/evrepo/api//agent/CG_50091_EP170474609917003", "id": "CG-PCER-AGENT:CG_50091_EP170474609917003", "type": "Agent" }, "contributionDate": { "date": "2024/1/23", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0018", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000216", "id": "SEPIO:0000216", "label": "Pathogenic Moderate" }, "id": "0018", "label": "PP4", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://genboree.org/evrepo/api/interpretation/CA9871496/MONDO:0007064/114/el/0/1831/1833", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA9871496/MONDO:0007064/114/ci/CA9871496/MONDO:0007064/114.002", "contribution": [ { "agent": { "@id": "https://genboree.org/evrepo/api//agent/CG_50091_EP170474609917003", "id": "CG-PCER-AGENT:CG_50091_EP170474609917003", "type": "Agent" }, "comments": "PMID: 19830125: 14-month-old Arab boy: Family history of SCID 0.5pts + T-B-NK- profile 0.5pts + Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5pts + Reduced ADA enzyme activity 1pt, total=2pts, PP4_Moderate", "contributionDate": { "date": "2024/1/23", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA9871496/MONDO:0007064/114/ci/CA9871496/MONDO:0007064/114.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA9871496/MONDO:0007064/114/0/1831/1833", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA9871496/MONDO:0007064/114/1/1832", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA9871496/MONDO:0007064/114/0/1831", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA9871496/MONDO:0007064/114", "metadata": { "created": "2024-09-23T21:53:35.457Z", "note": "DISCLAIMER: While the data/content in this document is approved by ClinGen expert panel(s), the SEPIO schema presented here is an initial prototype and has not been reviewed nor finalized by the ClinGen Data Exchange Modeling Team. We expect it to differ significantly from the final schema.", "producedAtUTC": "Mon, 23 Sep 2024 21:53:35 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "1.0.0" }, "statementOutcome": { "@id": "https://loinc.org/LA6668-3", "id": "LN:LA6668-3", "label": "Pathogenic" }, "type": "VariantPathogenicityInterpretation", "uuid": "c2cf447a-486b-46db-9aec-0c3e8f56633d", "variant": { "@id": "https://reg.genome.network/allele/CA9871496", "id": "CAR:CA9871496", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000022.4:c.845G>A" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000022.4(ADA):c.845G>A (p.Arg282Gln)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://genboree.org/evrepo/api/summarysrvc", "when": "2026-05-09T16:14:10.501Z" } }, "status": { "code": 200, "name": "OK" } }