{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/2ec7722b-a6c2-463a-aa7e-28c6c77f9d07/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/643243141", "label": "ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F8 Version 1.0.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "1.0.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0010602", "id": "MONDO:0010602", "label": "hemophilia A", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA519384276/MONDO:0010602/071/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA519384276/MONDO:0010602/071/ei/1/1748", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "contributionDate": { "date": "2025/12/23", "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" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA519384276/MONDO:0010602/071/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA519384276/MONDO:0010602/071/ci/CA519384276/MONDO:0010602/071.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "comments": "The variant has a SpliceAI score of: 0.06, 0.05, 0, 0. This is below the threshold for PP3 (>0.5), but above the threshold for BP4 (<0.05). ", "contributionDate": { "date": "2025/12/23", "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": "CA519384276/MONDO:0010602/071/ci/CA519384276/MONDO:0010602/071.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA519384276/MONDO:0010602/071/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA519384276/MONDO:0010602/071/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA519384276/MONDO:0010602/071/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA519384276/MONDO:0010602/071/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA519384276/MONDO:0010602/071/ei/1/1634", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "contributionDate": { "date": "2025/12/23", "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" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA519384276/MONDO:0010602/071/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA519384276/MONDO:0010602/071/ci/CA519384276/MONDO:0010602/071.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "comments": "1 patient in MLOF with a FVIII level of 26%, which typically counts at PP4_moderate, however PP4 points cannot be applied due to the variant meeting BS1. ", "contributionDate": { "date": "2025/12/23", "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": "CA519384276/MONDO:0010602/071/ci/CA519384276/MONDO:0010602/071.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA519384276/MONDO:0010602/071/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA519384276/MONDO:0010602/071/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA519384276/MONDO:0010602/071/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA519384276/MONDO:0010602/071/el/0/1684", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA519384276/MONDO:0010602/071/ei/1/1685", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "contributionDate": { "date": "2025/12/23", "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" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA519384276/MONDO:0010602/071/el/0/1684/1686", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA519384276/MONDO:0010602/071/ci/CA519384276/MONDO:0010602/071.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "contributionDate": { "date": "2025/12/23", "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": "CA519384276/MONDO:0010602/071/ci/CA519384276/MONDO:0010602/071.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA519384276/MONDO:0010602/071/0/1684/1686", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA519384276/MONDO:0010602/071/1/1685", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA519384276/MONDO:0010602/071/0/1684", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA519384276/MONDO:0010602/071/el/0/1735", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA519384276/MONDO:0010602/071/ei/1/1736", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "contributionDate": { "date": "2025/12/23", "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" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA519384276/MONDO:0010602/071/el/0/1735/1737", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA519384276/MONDO:0010602/071/ci/CA519384276/MONDO:0010602/071.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "comments": "This variant has been reported in at least nine males with mild hemophilia A (PMIDs: 35770352, 35743412, 30690819; Fernández-Artazcoz (2024), and Internal Laboratory Data), including at least one patient who underwent comprehensive testing with F8 sequencing and CNV analysis, and at least one patient with type 2N von Willebrand disease excluded by normal 2N binding. Patients have also been reported with reduced factor VIII activity levels >40% (PMIDs: 25652415, Fernández-Artazcoz (2024)), indicating that the variant is associated with a spectrum of factor VIII reduction extending into the low-normal range. Of note, PS4 points have not been applied due to this variant meeting BS1. \n\nFernández-Artazcoz (2024) can be accessed here: https://www.postersessiononline.eu/173580348_eu/congresos/WFH2024/aula/-PO_32_WFH2024.pdf", "contributionDate": { "date": "2025/12/23", "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": "CA519384276/MONDO:0010602/071/ci/CA519384276/MONDO:0010602/071.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA519384276/MONDO:0010602/071/0/1735/1737", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA519384276/MONDO:0010602/071/1/1736", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA519384276/MONDO:0010602/071/0/1735", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA519384276/MONDO:0010602/071/el/0/1594", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA519384276/MONDO:0010602/071/ei/1/1595", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "contributionDate": { "date": "2025/12/23", "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" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA519384276/MONDO:0010602/071/el/0/1594/1596", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA519384276/MONDO:0010602/071/ci/CA519384276/MONDO:0010602/071.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "comments": "This variant may alter normal splicing and result in transcripts lacking exon 2, introducing a frameshift and premature termination codon predicted to undergo nonsense mediated decay (p.Phe30Serfs*7).\n\nPatient mRNA analyses show variable splicing patterns, with some samples containing both full length and exon 2 skipped transcripts, while others predominantly express the wildtype transcript. (PMIDs: 25652415, 34962362, 23088352). This variability is consistent with incomplete or leaky splicing, likely reflecting differences in individual sensitivity to the splice defect. Such variability in splicing efficiency corresponds with the variable reduction in factor VIII levels observed among patients, ranging from normal to mildly decreased.\n\nA minigene assay showed normal exon 2 splicing for c.222G>A in HeLa and in Huh7 hepatocyte derived cells (PMID: 30690819).\n\nDue to conflicting evidence, PVS1 has not been applied at any strength. ", "contributionDate": { "date": "2025/12/23", "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": "CA519384276/MONDO:0010602/071/ci/CA519384276/MONDO:0010602/071.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA519384276/MONDO:0010602/071/0/1594/1596", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA519384276/MONDO:0010602/071/1/1595", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA519384276/MONDO:0010602/071/0/1594", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA519384276/MONDO:0010602/071/el/0/1804", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA519384276/MONDO:0010602/071/ei/1/1805", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "contributionDate": { "date": "2025/12/23", "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" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA519384276/MONDO:0010602/071/el/0/1804/1806", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA519384276/MONDO:0010602/071/ci/CA519384276/MONDO:0010602/071.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "comments": "The Grpmax filtering AF in gnomad V4.1.0 is 0.0001184 (meets BS1) with greater than 45000 alleles tested for the subpopulation in which this variant was detected (Admixed American).", "contributionDate": { "date": "2025/12/23", "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": "CA519384276/MONDO:0010602/071/ci/CA519384276/MONDO:0010602/071.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA519384276/MONDO:0010602/071/0/1804/1806", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA519384276/MONDO:0010602/071/1/1805", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA519384276/MONDO:0010602/071/0/1804", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA519384276/MONDO:0010602/071/el/0/1654", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA519384276/MONDO:0010602/071/ei/1/1655", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "contributionDate": { "date": "2025/12/23", "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" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA519384276/MONDO:0010602/071/el/0/1654/1656", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA519384276/MONDO:0010602/071/ci/CA519384276/MONDO:0010602/071.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "comments": "The variant has a PhyloP 100 vertebrate score of -1.16, which suggests it is not conserved, however this variant does not meet BP4 requirements and therefore BP7 cannot be applied. ", "contributionDate": { "date": "2025/12/23", "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": "CA519384276/MONDO:0010602/071/ci/CA519384276/MONDO:0010602/071.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA519384276/MONDO:0010602/071/0/1654/1656", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA519384276/MONDO:0010602/071/1/1655", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA519384276/MONDO:0010602/071/0/1654", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA519384276/MONDO:0010602/071", "metadata": { "created": "2025-12-23T15:05:04.154Z", "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": "Tue, 23 Dec 2025 15:05:04 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "1.0.0" }, "statementOutcome": { "@id": "https://loinc.org/LA26333-7", "id": "LN:LA26333-7", "label": "Uncertain Significance" }, "type": "VariantPathogenicityInterpretation", "uuid": "2ec7722b-a6c2-463a-aa7e-28c6c77f9d07", "variant": { "@id": "https://reg.genome.network/allele/CA519384276", "id": "CAR:CA519384276", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000132.4:c.222G>A" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000132.4(F8):c.222G>A (p.Thr74=)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-14T09:31:35.717Z" } }, "status": { "code": 200, "name": "OK" } }