{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/2d1eb815-6c23-4456-b617-5f09db470564/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1562840326", "label": "ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for FOXN1 Version 1.0.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "1.0.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0011132", "id": "MONDO:0011132", "label": "T-cell immunodeficiency, congenital alopecia, and nail dystrophy", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8459424/MONDO:0011132/113/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8459424/MONDO:0011132/113/ei/1/1637", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "contributionDate": { "date": "2024/9/27", "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://erepo.genome.network/evrepo/api/interpretation/CA8459424/MONDO:0011132/113/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA8459424/MONDO:0011132/113/ci/CA8459424/MONDO:0011132/113.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "comments": "The variant has a gnomADv4.1 Grpmax filtering allele frequency of 0.000003590, which is based upon the European (non-Finnish) population (9/1180006 alleles), which is lower than the ClinGen SCID VCEP threshold (≤0.00002412) for PM2_Supporting,", "contributionDate": { "date": "2024/9/27", "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": "CA8459424/MONDO:0011132/113/ci/CA8459424/MONDO:0011132/113.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA8459424/MONDO:0011132/113/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8459424/MONDO:0011132/113/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA8459424/MONDO:0011132/113/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8459424/MONDO:0011132/113/el/0/1828", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8459424/MONDO:0011132/113/ei/1/1829", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "contributionDate": { "date": "2024/9/27", "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/0052", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000330", "id": "SEPIO:0000330", "label": "Pathogenic Strong" }, "id": "0052", "label": "PS3", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8459424/MONDO:0011132/113/el/0/1828/1830", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA8459424/MONDO:0011132/113/ci/CA8459424/MONDO:0011132/113.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "comments": "The p.Pro350Leu variant showed significantly reduced activity in a luciferase assay (<50%) from PMID: 33464451, though the variant showed only partial loss of function (88%) in another luciferase assay as part of a validated assay with pathogenic and benign controls (PMID: 37419334).", "contributionDate": { "date": "2024/9/27", "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": "CA8459424/MONDO:0011132/113/ci/CA8459424/MONDO:0011132/113.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA8459424/MONDO:0011132/113/0/1828/1830", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8459424/MONDO:0011132/113/1/1829", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA8459424/MONDO:0011132/113/0/1828", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8459424/MONDO:0011132/113/el/0/1609", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8459424/MONDO:0011132/113/ei/1/1610", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "contributionDate": { "date": "2024/9/27", "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/0027", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0027", "label": "PM3", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8459424/MONDO:0011132/113/el/0/1609/1611", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA8459424/MONDO:0011132/113/ci/CA8459424/MONDO:0011132/113.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "comments": "The patient (P9 of PMID: 33464451) is compound heterozygous with pathogenic variant NM_001369369.1(FOXN1):c.246C>A (p.Cys82Ter), confirmation of trans phase not reported (0.5pt; PM3_supporting)\t", "contributionDate": { "date": "2024/9/27", "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": "CA8459424/MONDO:0011132/113/ci/CA8459424/MONDO:0011132/113.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA8459424/MONDO:0011132/113/0/1609/1611", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8459424/MONDO:0011132/113/1/1610", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA8459424/MONDO:0011132/113/0/1609", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8459424/MONDO:0011132/113/el/0/1615", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8459424/MONDO:0011132/113/ei/1/1616", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "contributionDate": { "date": "2024/9/27", "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/006", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000216", "id": "SEPIO:0000216", "label": "Pathogenic Moderate" }, "id": "006", "label": "PM1", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8459424/MONDO:0011132/113/el/0/1615/1617", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA8459424/MONDO:0011132/113/ci/CA8459424/MONDO:0011132/113.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "comments": "This variant is found in the DNA binding forkhead domain (amino acids 270-367), which is a well-established functional domain (Newman et al., 2020; PMID: 31914405) of FOXN1, which has low tolerance for benign variation (PM1).", "contributionDate": { "date": "2024/9/27", "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": "CA8459424/MONDO:0011132/113/ci/CA8459424/MONDO:0011132/113.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA8459424/MONDO:0011132/113/0/1615/1617", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8459424/MONDO:0011132/113/1/1616", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA8459424/MONDO:0011132/113/0/1615", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8459424/MONDO:0011132/113/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8459424/MONDO:0011132/113/ei/1/1748", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "contributionDate": { "date": "2024/9/27", "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/0062", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0062", "label": "PP3", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8459424/MONDO:0011132/113/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA8459424/MONDO:0011132/113/ci/CA8459424/MONDO:0011132/113.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "comments": "The computational predictor REVEL gives a score of 0.893, which is above the threshold of\n≥0.644, evidence that correlates with impact to FOXN1 function (PP3)", "contributionDate": { "date": "2024/9/27", "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": "CA8459424/MONDO:0011132/113/ci/CA8459424/MONDO:0011132/113.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA8459424/MONDO:0011132/113/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8459424/MONDO:0011132/113/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA8459424/MONDO:0011132/113/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8459424/MONDO:0011132/113/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8459424/MONDO:0011132/113/ei/1/1634", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "contributionDate": { "date": "2024/9/27", "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/0063", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0063", "label": "PP4", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8459424/MONDO:0011132/113/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA8459424/MONDO:0011132/113/ci/CA8459424/MONDO:0011132/113.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "comments": "At least one patient (P9 of PMID: 33464451) with this variant displayed alopecia (0.25 pts) and low t-cell numbers (less than 1,000,000 cells/L; 0.5pts). The patient had whole exome sequencing (0.5pt) Total 1.25pt (PP4).\n\nThe patient also had poor proliferative response to phytohemagglutinin on total cells, while it was normal when evaluated on separated T cells, flow cytometric analysis showed near complete absence of CD45RA+ CD4 T cells, and they had very low TRECs. They received a thymus transplant but T cell levels were not reported post transplant. Interestingly the patients alopecia spontaneously reversed at age 3.", "contributionDate": { "date": "2024/9/27", "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": "CA8459424/MONDO:0011132/113/ci/CA8459424/MONDO:0011132/113.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA8459424/MONDO:0011132/113/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8459424/MONDO:0011132/113/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA8459424/MONDO:0011132/113/0/1633", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8459424/MONDO:0011132/113", "metadata": { "created": "2024-09-28T06:07:26.795Z", "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": "Sat, 28 Sep 2024 06:07:26 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "1.0.0" }, "statementOutcome": { "@id": "https://loinc.org/LA26332-9", "id": "LN:LA26332-9", "label": "Likely Pathogenic" }, "type": "VariantPathogenicityInterpretation", "uuid": "2d1eb815-6c23-4456-b617-5f09db470564", "variant": { "@id": "https://reg.genome.network/allele/CA8459424", "id": "CAR:CA8459424", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_001369369.1:c.1049C>T" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_001369369.1(FOXN1):c.1049C>T (p.Pro350Leu)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-05T05:58:06.464Z" } }, "status": { "code": 200, "name": "OK" } }