{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/491bbc8e-a398-41a7-8fa1-5ab562f996c1/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1527859052", "label": "ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 2.0.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "2.0.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0010604", "id": "MONDO:0010604", "label": "hemophilia B", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA414435594/MONDO:0010604/080/el/0/1828", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA414435594/MONDO:0010604/080/ei/1/1829", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "contributionDate": { "date": "2026/4/12", "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/CA414435594/MONDO:0010604/080/el/0/1828/1830", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA414435594/MONDO:0010604/080/ci/CA414435594/MONDO:0010604/080.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "comments": "The p.Arg46Ser variant was assessed in a cell-based reporter assay in HEK293T cells and was associated with a severely reduced secreted conformation-specific reporter (SCSR) signal, consistent with markedly reduced secretion of properly processed functional reporter protein (PMID: 32766856). Of note, because the assay was performed at the protein level, it is unclear whether the p.Arg46Ser construct corresponds specifically to c.138G>C or c.138G>T, as both encode the same amino acid change and both variants are cited. PS3 evidence was not applied because additional published studies indicate that this variant causes abnormal splicing, making it unclear to what extent any observed functional effect is attributable to the missense change itself.", "contributionDate": { "date": "2026/4/12", "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": "CA414435594/MONDO:0010604/080/ci/CA414435594/MONDO:0010604/080.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA414435594/MONDO:0010604/080/0/1828/1830", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA414435594/MONDO:0010604/080/1/1829", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA414435594/MONDO:0010604/080/0/1828", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA414435594/MONDO:0010604/080/el/0/1699", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA414435594/MONDO:0010604/080/ei/1/1700", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "contributionDate": { "date": "2026/4/12", "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/CA414435594/MONDO:0010604/080/el/0/1699/1701", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA414435594/MONDO:0010604/080/ci/CA414435594/MONDO:0010604/080.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "comments": "At least 3 probands from the literature and internal laboratory data meet F9 phenotype criteria (PMID: 25251685, PMID: 3461460, PMID: 7937052). ", "contributionDate": { "date": "2026/4/12", "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": "CA414435594/MONDO:0010604/080/ci/CA414435594/MONDO:0010604/080.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA414435594/MONDO:0010604/080/0/1699/1701", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA414435594/MONDO:0010604/080/1/1700", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA414435594/MONDO:0010604/080/0/1699", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA414435594/MONDO:0010604/080/el/0/1786", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA414435594/MONDO:0010604/080/ei/1/1787", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "contributionDate": { "date": "2026/4/12", "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/CA414435594/MONDO:0010604/080/el/0/1786/1788", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA414435594/MONDO:0010604/080/ci/CA414435594/MONDO:0010604/080.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "comments": "The Arg46Ser variant is a consequence of c.138G>T and c.138G>C. The c.138G>T variant is reported in moderate-severe HB patients. Both variants alter splicing.", "contributionDate": { "date": "2026/4/12", "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": "CA414435594/MONDO:0010604/080/ci/CA414435594/MONDO:0010604/080.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA414435594/MONDO:0010604/080/0/1786/1788", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA414435594/MONDO:0010604/080/1/1787", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA414435594/MONDO:0010604/080/0/1786", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA414435594/MONDO:0010604/080/el/0/1594", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA414435594/MONDO:0010604/080/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": "2026/4/12", "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/CA414435594/MONDO:0010604/080/el/0/1594/1596", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA414435594/MONDO:0010604/080/ci/CA414435594/MONDO:0010604/080.002", "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 is located within an exonic splicing silencer, and RT-PCR minigene assays performed in BHK cells demonstrated that c.138G>C was associated with abnormal splicing due to increased use of an exonic cryptic 5′ splice site, resulting in an out-of-frame transcript with a premature termination codon (PMID: 26063760). ", "contributionDate": { "date": "2026/4/12", "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": "CA414435594/MONDO:0010604/080/ci/CA414435594/MONDO:0010604/080.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA414435594/MONDO:0010604/080/0/1594/1596", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA414435594/MONDO:0010604/080/1/1595", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA414435594/MONDO:0010604/080/0/1594", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA414435594/MONDO:0010604/080/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA414435594/MONDO:0010604/080/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": "2026/4/12", "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/CA414435594/MONDO:0010604/080/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA414435594/MONDO:0010604/080/ci/CA414435594/MONDO:0010604/080.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "comments": "The missense variant has a REVEL score of 0.802 (>0.6). SpliceAI predicts a cryptic donor gain with a score of 0.13 but does not meet the threshold of >0.5. Code is not used because PVS1_RNA is applied.", "contributionDate": { "date": "2026/4/12", "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": "CA414435594/MONDO:0010604/080/ci/CA414435594/MONDO:0010604/080.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA414435594/MONDO:0010604/080/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA414435594/MONDO:0010604/080/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA414435594/MONDO:0010604/080/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA414435594/MONDO:0010604/080/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA414435594/MONDO:0010604/080/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": "2026/4/12", "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/CA414435594/MONDO:0010604/080/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA414435594/MONDO:0010604/080/ci/CA414435594/MONDO:0010604/080.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "comments": "There are no known reported cases with deletion/duplication reported.", "contributionDate": { "date": "2026/4/12", "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": "CA414435594/MONDO:0010604/080/ci/CA414435594/MONDO:0010604/080.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA414435594/MONDO:0010604/080/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA414435594/MONDO:0010604/080/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA414435594/MONDO:0010604/080/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA414435594/MONDO:0010604/080/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA414435594/MONDO:0010604/080/ei/1/1637", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "contributionDate": { "date": "2026/4/12", "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/CA414435594/MONDO:0010604/080/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA414435594/MONDO:0010604/080/ci/CA414435594/MONDO:0010604/080.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "comments": "The c.138G>C (p.Arg46Ser) variant is completely absent from population databases (gnomAD v4.1.0).", "contributionDate": { "date": "2026/4/12", "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": "CA414435594/MONDO:0010604/080/ci/CA414435594/MONDO:0010604/080.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA414435594/MONDO:0010604/080/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA414435594/MONDO:0010604/080/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA414435594/MONDO:0010604/080/0/1636", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA414435594/MONDO:0010604/080", "metadata": { "created": "2026-04-12T17:05:03.799Z", "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": "Sun, 12 Apr 2026 17:05:03 -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": "491bbc8e-a398-41a7-8fa1-5ab562f996c1", "variant": { "@id": "https://reg.genome.network/allele/CA414435594", "id": "CAR:CA414435594", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_001313913.2:c.138G>C" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_001313913.2:c.138G>C" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-31T11:40:00.633Z" } }, "status": { "code": 200, "name": "OK" } }