Variant: NM_000133.3(F9):c.835G>A (p.Ala279Thr)

CA277507

216926 (ClinVar)

Gene: F9

Condition: hemophilia B

Inheritance Mode: X-linked inheritance

UUID: 4982024e-218e-4597-8dff-d780dd246d0a

Approved on: 2024-02-09

Published on: 2024-07-11

HGVS expressions

NM_000133.3:c.835G>A
NM_000133.3(F9):c.835G>A (p.Ala279Thr)
NC_000023.11:g.139560852G>A
CM000685.2:g.139560852G>A
NC_000023.10:g.138643011G>A
CM000685.1:g.138643011G>A
NC_000023.9:g.138470677G>A
NG_007994.1:g.35117G>A
ENST00000218099.7:c.835G>A
ENST00000643157.1:n.1502G>A
ENST00000218099.6:c.835G>A
ENST00000394090.2:c.721G>A
NM_001313913.1:c.721G>A
NM_000133.4:c.835G>A
NM_001313913.2:c.721G>A

Pathogenic

• Met criteria codes: PM2_Supporting PP4_Moderate PS4 PM1 PP3

• Not Met criteria codes: PP1

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

Evidence submitted by expert panel

Coagulation Factor Deficiency VCEP

The NM_000133.3:c.835G>A variant that results in the Ala279Thr missense change is absent from gnomAD v2.1.1 and v3, meeting PM2_Supporting. It is located within the peptidase S2 domain, which is deemed critical to protein function, meeting PM1. More than 59 male patients with mild hemophilia B are reported hemizygous for this variant in the literature, meeting PS4_Very strong and PP4_Moderate criteria (PMID: 29296726, 29656491). It is noted as a founder variant but may also have arisen de novo as a recurrent variant and is found in multiple ethnicities. The variant has a REVEL score of 0.765 (>0.6) and CADD score of 23 (>21) which meet the thresholds recommended for PP3. In summary, the variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4_Very Strong, PM1, PP3, PP4_Moderate, PM2_Supporting.

Met criteria codes

• PM2_Supporting: The variant is absent from gnomAD v2.1.1 and v3.
• PP4_Moderate: Male with mild hemophilia B with 6% factor IX activity level who had F8 and F9 full gene sequencing and deletion/duplication analysis.
• PS4: At least 59 patients with the Ala279Thr variant are reported across 27 publications from different ethnicities, meeting criteria for PS4_Very Strong. This is a conservative estimate, it is likely that the variant is present at a higher frequency among HB patients. 94 HB patients are recorded in the EAHAD database. The variant is mostly associated with mild disease, with a mean FIX:C of 11.21 U/dl (PMID: 19699296). Inhibitors are NOT reported in patients.
• PM1: The variant at position 279 occurs within the peptidase S1 domain, which is determined by the CFD VCEP to be critical to the function of the F9 protein
• PP3: REVEL score of 0.765 (>0.6) and CADD score of 23 (>21) meet the thresholds recommended for PP3 by the CFD VCEP

Not Met criteria codes

• PP1: From internal laboratory data: Patient with mild HB (FIX:C = 19%) is reported to have two brothers with HB; however, their genotyping information is unavailable.