Evidence Repository
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.1304G>A (p.Cys435Tyr)

CA414447219

811512 (ClinVar)

Gene: F9
Condition: hemophilia B
Inheritance Mode: X-linked inheritance
Link to MONDO
UUID: 34515d58-87f3-4b05-9308-5a3ca86ded96
Approved on: 2024-05-09
Published on: 2024-07-11

HGVS expressions

NM_000133.4:c.1304G>A
NM_000133.4(F9):c.1304G>A (p.Cys435Tyr)
NC_000023.11:g.139561989G>A
CM000685.2:g.139561989G>A
NC_000023.10:g.138644148G>A
CM000685.1:g.138644148G>A
NC_000023.9:g.138471814G>A
NG_007994.1:g.36254G>A
ENST00000218099.7:c.1304G>A
ENST00000643157.1:n.1723+248G>A
ENST00000218099.6:c.1304G>A
ENST00000394090.2:c.1190G>A
NM_000133.3:c.1304G>A
NM_001313913.1:c.1190G>A
NM_001313913.2:c.1190G>A

Pathogenic

Met criteria codes 5
PS4 PP4 PP1 PP3 PM2_Supporting
Not Met criteria codes 1
PM1

Evidence Links 0

Expert Panel

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 NM_000133.4:c.1304G>A variant in F9 is a missense variant predicted to cause substitution of Cys by Tyr at amino acid 435 (p.Cys435Tyr). This variant has been reported in 9 probands meeting F9 phenotype criteria (PS4_Very Strong, PP4; PMIDs: s: 8091381, 10698280, 29296726, 22103590, 21118338, 8217825, 7482402). The variant has been reported to segregate with hemophilia B in 2 affected family members from 1 family (PP1; PMID: 21118338). The computational predictor REVEL gives a score of 0.943, which is above the threshold of 0.6, evidence that correlates with impact to F9 function (PP3). This variant is absent from gnomAD v2, v3 and v4. In summary, this variant meets the criteria to be classified as pathogenic for hemophilia B based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP: PS4_Very Strong, PM2_Supporting, PP4, PP3, PP1. (Version 1.0.0, 10/05/2023)
Met criteria codes
PS4
8 probands with varying severity of hemophilia B are reported across the literature (PMIDs: 8091381, 10698280, 29296726, 22103590, 21118338, 8217825, 7482402), meeting criteria for PS4_Very Strong.
PP4
At least one patient with this variant displayed severe factor IX deficiency, which is highly specific for hemophilia B (PP4, PMID: 29296726)
PP1
Variant was identified in patient Hb7 and Hb8, who are related with severe hemophilia B, but relationship not defined so using at supporting level.
PP3
REVEL score is 0.943, which is above our cutoff for PP3.
PM2_Supporting
Variant is absent from v2.1.1 and V3.1.2.
Not Met criteria codes
PM1
Variant is outside of exons 3, 4, and 5.
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