Variant: NM_000132.3:c.1213A>T

CA414916097

Gene: F8

Condition: hemophilia A

Inheritance Mode: X-linked inheritance

UUID: d9542a46-0c68-4d4a-8ee3-397e73523366

Approved on: 2024-06-19

Published on: 2024-07-11

HGVS expressions

NM_000132.3:c.1213A>T
NC_000023.11:g.154966484T>A
CM000685.2:g.154966484T>A
NC_000023.10:g.154194759T>A
CM000685.1:g.154194759T>A
NC_000023.9:g.153847953T>A
NG_011403.1:g.61240A>T
NG_011403.2:g.61240A>T
ENST00000360256.9:c.1213A>T
ENST00000647125.1:c.*1089A>T
ENST00000360256.8:c.1213A>T
ENST00000483822.2:n.33A>T
NM_000132.4:c.1213A>T

Uncertain Significance

• Met criteria codes: PM5_Supporting PS4_Moderate PM2_Supporting PP3

• Not Met criteria codes: PM1

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

Evidence submitted by expert panel

Coagulation Factor Deficiency VCEP

The variant, NM_000132.3:c.1213A>T predicts a missense change, Ile405Phe, that is absent from gnomAD v2.1.1 and v3 (PM2_Supporting). This variant has been reported in at least two patients with moderate Hemophilia A in the literature (PS4_Moderate, PMID: 10404764 and 18691168). The variant has a REVEL score of 0.927 (PP3, threshold >0.6). Another variant at the same codon, Ile405Thr, is curated by the Coagulation Factor Deficiency Variant Curation Expert Panel as likely pathogenic (PM5_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4_Moderate, PP3, PM2_Supporting, PM5_Supporting.

Met criteria codes

• PM5_Supporting: c.1214T>C (p.Ile405Thr) is a variant at the same codon and is curated by the Coagulation Factor Deficiency VCEP to be likely pathogenic, meeting criteria for PM5_Supporting.
• PS4_Moderate: 2 patients are reported in PMID: 10404764 and 18691168 who meet F8 phenotype criteria.
• PM2_Supporting: Ile405Phe is absent from gnomAD v2 and v3.
• PP3: REVEL score of 0.927 (threshold: >0.6) and CADD score of 24.6 (threshold: >21) meet criteria for PP3

Not Met criteria codes

• PM1: Ile405Phe occurs in the A2 domain. PM1 is not applied at this time.