{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/23a1f723-f975-46ee-b42a-01ececf77079/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1745574676", "label": "ClinGen Hemoglobinopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HBB Version 1.0.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "1.0.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0013517", "id": "MONDO:0013517", "label": "beta-thalassemia HBB/LCRB", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA124983/MONDO:0013517/170/el/0/1699", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA124983/MONDO:0013517/170/ei/1/1700", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "contributionDate": { "date": "2026/4/7", "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/CA124983/MONDO:0013517/170/el/0/1699/1701", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA124983/MONDO:0013517/170/ci/CA124983/MONDO:0013517/170.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "comments": "This variant has been reported in [12] unrelated probands meeting [beta thalassemia trait]. Total score is 2.15 [PMID: 7104238, PMID:3955238 and internal lab contributors].\n\n", "contributionDate": { "date": "2026/4/7", "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": "CA124983/MONDO:0013517/170/ci/CA124983/MONDO:0013517/170.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA124983/MONDO:0013517/170/0/1699/1701", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA124983/MONDO:0013517/170/1/1700", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA124983/MONDO:0013517/170/0/1699", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA124983/MONDO:0013517/170/el/0/1717", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA124983/MONDO:0013517/170/ei/1/1718", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "contributionDate": { "date": "2026/4/7", "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/CA124983/MONDO:0013517/170/el/0/1717/1719", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA124983/MONDO:0013517/170/ci/CA124983/MONDO:0013517/170.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "comments": "This variant has been detected in 2 individuals with a beta-thalassemia intermedia phenotype. Of those individuals, 1 was compound heterozygous for the variant and a pathogenic variant (β0 IVSII-I G>C), confirmed in trans by family testing and DNA studies, and the other was homozygous for the variant. Total PM3 points: 1.5 [PMID:3955238, PMID:25332589; VCV000015438.38].\n\n", "contributionDate": { "date": "2026/4/7", "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": "CA124983/MONDO:0013517/170/ci/CA124983/MONDO:0013517/170.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA124983/MONDO:0013517/170/0/1717/1719", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA124983/MONDO:0013517/170/1/1718", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA124983/MONDO:0013517/170/0/1717", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA124983/MONDO:0013517/170/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA124983/MONDO:0013517/170/ei/1/1781", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "contributionDate": { "date": "2026/4/7", "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/CA124983/MONDO:0013517/170/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA124983/MONDO:0013517/170/ci/CA124983/MONDO:0013517/170.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "comments": "Two different missense variants [c.83C>T (p.Ala28Val); c.83C>A (p.Ala28Asp)] in the same codon have been reported in patients with haemoglobinopathy [VCV000015184.2; VCV000015386.3]. However, these variants have not yet met the criteria to be classified as pathogenic by the ClinGen Hemoglobinopathy VCEP/(or) with a 2-star review status by ClinVar.", "contributionDate": { "date": "2026/4/7", "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": "CA124983/MONDO:0013517/170/ci/CA124983/MONDO:0013517/170.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA124983/MONDO:0013517/170/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA124983/MONDO:0013517/170/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA124983/MONDO:0013517/170/0/1780", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA124983/MONDO:0013517/170/el/0/1696", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA124983/MONDO:0013517/170/ei/1/1697", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "contributionDate": { "date": "2026/4/7", "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/CA124983/MONDO:0013517/170/el/0/1696/1698", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA124983/MONDO:0013517/170/ci/CA124983/MONDO:0013517/170.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "comments": "Globin biosynthesis showed an β/α ratio to be between 0.45-0.55 indicating that this variant impacts protein function [PMID: 7104238 and PMID:7173395].\n[In vitro spicing assay] demonstrated that the variant impacts splicing by [ creating a cryptic donor region of exon 1] [PMID:6733281].\n\n", "contributionDate": { "date": "2026/4/7", "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": "CA124983/MONDO:0013517/170/ci/CA124983/MONDO:0013517/170.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA124983/MONDO:0013517/170/0/1696/1698", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA124983/MONDO:0013517/170/1/1697", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA124983/MONDO:0013517/170/0/1696", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA124983/MONDO:0013517/170/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA124983/MONDO:0013517/170/ei/1/1637", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "contributionDate": { "date": "2026/4/7", "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/CA124983/MONDO:0013517/170/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA124983/MONDO:0013517/170/ci/CA124983/MONDO:0013517/170.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "comments": "The minor allele frequency in gnomAD v4.1 is 0.000002479 (4/1613406) alleles, which is lower than the ClinGen Hemoglobinopathy VCEP threshold <0.0001 for PM2_Supporting, and therefore meets this criterion.", "contributionDate": { "date": "2026/4/7", "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": "CA124983/MONDO:0013517/170/ci/CA124983/MONDO:0013517/170.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA124983/MONDO:0013517/170/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA124983/MONDO:0013517/170/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA124983/MONDO:0013517/170/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA124983/MONDO:0013517/170/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA124983/MONDO:0013517/170/ei/1/1748", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "contributionDate": { "date": "2026/4/7", "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/CA124983/MONDO:0013517/170/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA124983/MONDO:0013517/170/ci/CA124983/MONDO:0013517/170.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "comments": "The computational predictor SpliceAI gives a Δ score of 0.79 for donor gain in exon 3, which is above threshold >0.3, predicting that the variant may affect splicing by disrupting the donor splice site of intron 3 in HBB.", "contributionDate": { "date": "2026/4/7", "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": "CA124983/MONDO:0013517/170/ci/CA124983/MONDO:0013517/170.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA124983/MONDO:0013517/170/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA124983/MONDO:0013517/170/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA124983/MONDO:0013517/170/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA124983/MONDO:0013517/170/el/0/1648", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA124983/MONDO:0013517/170/ei/1/1649", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "contributionDate": { "date": "2026/4/7", "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/CA124983/MONDO:0013517/170/el/0/1648/1650", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA124983/MONDO:0013517/170/ci/CA124983/MONDO:0013517/170.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "comments": "The variant has been reported to segregate with [beta thalassemia ] in [8] affected family members from [4] families. The total number of unaffected segregations is [8]. The LOD score is [5.81] [PMIDs:7104238; 3955238; 25332589; 30777047;17949282]\n", "contributionDate": { "date": "2026/4/7", "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": "CA124983/MONDO:0013517/170/ci/CA124983/MONDO:0013517/170.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA124983/MONDO:0013517/170/0/1648/1650", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA124983/MONDO:0013517/170/1/1649", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA124983/MONDO:0013517/170/0/1648", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA124983/MONDO:0013517/170", "metadata": { "created": "2026-04-07T13:53:48.388Z", "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, 07 Apr 2026 13:49:06 -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": "23a1f723-f975-46ee-b42a-01ececf77079", "variant": { "@id": "https://reg.genome.network/allele/CA124983", "id": "CAR:CA124983", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000518.5:c.82G>T" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000518.5(HBB):c.82G>T (p.Ala28Ser)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-14T16:03:04.748Z" } }, "status": { "code": 200, "name": "OK" } }