Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001313913.2:c.1121G>A

CA414446709

2775451 (ClinVar)

Gene: F9 (HGNC:2158)

Condition: hemophilia B (MONDO:0010604)

Inheritance Mode: X-linked inheritance

UUID: 45aad5b1-fcb9-4818-8df5-a5b8fe03662b

Approved on: 2024-02-09

Published on: 2024-07-11

HGVS expressions

NM_001313913.2:c.1121G>A

NC_000023.11:g.139561920G>A

CM000685.2:g.139561920G>A

NC_000023.10:g.138644079G>A

CM000685.1:g.138644079G>A

NC_000023.9:g.138471745G>A

NG_007994.1:g.36185G>A

ENST00000218099.7:c.1235G>A

ENST00000643157.1:n.1723+179G>A

ENST00000218099.6:c.1235G>A

ENST00000394090.2:c.1121G>A

NM_000133.3:c.1235G>A

NM_001313913.1:c.1121G>A

NM_000133.4:c.1235G>A

Pathogenic

PP4_Moderate PS4 PP3 PM2_Supporting

PM5

Evidence Links 0

Expert Panel

Coagulation Factor Deficiency VCEP

Criteria Specification Information

Criteria Specification: ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Coagulation Factor Deficiency VCEP

The c.1235G>A (NM_000133.4) variant in F9 is a missense variant predicted to cause substitution of Glycine by Glutamate at amino acid 412 (p.Gly412Glu). This variant has been reported in at least 8 probands meeting the hemophilia B phenotype criteria specified by the Coagulation Factor Deficiency VCEP (PS4_VeryStrong; PMID: 10874302, 29296726, 1680287, 8055323, 12588353). At least one patient with this variant meets the VCEP specification for PP4 (PP4_Moderate, MLOF study). This variant is absent from gnomAD v2.1.1 and v3.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.981, which is above the threshold of 0.6, evidence that correlates with impact to F9 function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for X-linked recessive hemophilia B based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP: PS4_VeryStrong, PP4_Moderate, PP3, PM2_Supporting. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 1.0.0., Released 10/5/2023)

PP4_Moderate

Male with severe hemophilia B with F8 and F9 full gene sequencing and deletion/duplication analysis.

PS4

This variant has been reported in at least 8 probands meeting the hemophilia B phenotype criteria specified by the Coagulation Factor Deficiency VCEP (PS4_VeryStrong; PMID: 10874302, 29296726, 1680287, 8055323, 12588353).

PP3

The computational predictor REVEL gives a score of 0.981, which is above the threshold of 0.6, evidence that correlates with impact to F9 function (PP3).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 and v3.1.1 (PM2_Supporting).

PM5

This criteria is met. However, this variant meets pathogenic without using this code, so it is no longer needed for this variant. Gly412Trp and Gly412Ala are two variants at the same residue that are curated by the CFD-VCEP to be VUS with 1 supporting code short of a likely pathogenic classification. PM5_Supporting is applied based on two "highly suspicious VUS" at the same residue.

Curation History

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