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]

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Variant: NM_000133.4(F9):c.1325G>A (p.Gly442Glu)

CA414447349

811513 (ClinVar)

Gene: F9

Condition: hemophilia B

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: 851a65a8-4458-40fe-9463-1134bce75b53

Approved on: 2024-05-09

Published on: 2024-05-09

HGVS expressions

NM_000133.4:c.1325G>A

NM_000133.4(F9):c.1325G>A (p.Gly442Glu)

NC_000023.11:g.139562010G>A

CM000685.2:g.139562010G>A

NC_000023.10:g.138644169G>A

CM000685.1:g.138644169G>A

NC_000023.9:g.138471835G>A

NG_007994.1:g.36275G>A

ENST00000218099.7:c.1325G>A

ENST00000643157.1:n.1723+269G>A

ENST00000218099.6:c.1325G>A

ENST00000394090.2:c.1211G>A

NM_000133.3:c.1325G>A

NM_001313913.1:c.1211G>A

NM_001313913.2:c.1211G>A

Likely Pathogenic

PS4_Moderate PM2_Supporting PP3 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 F8 Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Coagulation Factor Deficiency VCEP

The c.1325G>A (NM_000133.4) variant in F9 is a missense variant predicted to cause substitution of Glycine by Glutamate at amino acid 442 (p.Gly442Glu). This variant has been reported in at least 2 probands meeting the hemophilia B phenotype criteria specified by the Coagulation Factor Deficiency VCEP (PS4_Moderate; PMID: 12604421, 18624698). This variant is absent from gnomAD v2.1.1 and v3.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.908, which is above the threshold of 0.6, evidence that correlates with impact to F9 function (PP3). Another missense variant c.1234G>A, p.Gly442Arg in the same codon has been classified as pathogenic for hemophilia B by the ClinGen Coagulation Factor Deficiency VCEP (PM5). In summary, this variant meets the criteria to be classified as Likely Pathogenic for X-linked recessive hemophilia B based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP: PM5, PS4_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)

PS4_Moderate

This variant has been reported in at least 2 probands meeting the hemophilia B phenotype criteria specified by the Coagulation Factor Deficiency VCEP (PS4_Moderate; PMID: 12604421, 18624698).

PM2_Supporting

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

PP3

The computational predictor REVEL gives a score of 0.908, which is above the threshold of 0.6, evidence that correlates with impact to F9 function (PP3). SpliceAI predicts no impact on splicing with a delta score of 0.

PM5

Another missense variant c.1234G>A, p.Gly442Arg in the same codon has been classified as pathogenic for hemophilia B by the ClinGen Coagulation Factor Deficiency VCEP (PM5).

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