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]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_000132.3(F8):c.4121_4124del (p.Ile1374fs)

CA255148

10256 (ClinVar)

Gene: F8
Condition: hemophilia A
Inheritance Mode: X-linked inheritance
Link to MONDO
UUID: eec8143e-0a98-4734-9318-ab3c2cdc0c32
Approved on: 2024-02-09
Published on: 2024-07-11

HGVS expressions

NM_000132.3:c.4121_4124del
NM_000132.3(F8):c.4121_4124del (p.Ile1374fs)
NC_000023.11:g.154929669_154929672del
CM000685.2:g.154929669_154929672del
NC_000023.10:g.154157944_154157947del
CM000685.1:g.154157944_154157947del
NC_000023.9:g.153811138_153811141del
NG_011403.1:g.98055_98058del
NG_011403.2:g.98055_98058del
ENST00000360256.9:c.4121_4124del
ENST00000360256.8:c.4121_4124del
NM_000132.4:c.4121_4124del
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Pathogenic

Met criteria codes 3
PS4 PVS1 PM2_Supporting

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 F8 Version 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Coagulation Factor Deficiency VCEP
The NM_000132.3(F8):c.4121_4124del (p.Ile1374fs) variant is a frameshift variant that is predicted to introduce a premature stop codon in exon 14 and expected to result in nonsense-mediated mRNA decay, which meets PVS1. It is reported in at least 7 patients with moderate or severe hemophilia A in the literature reviewed (PMID: 22103590, 20102490, 8307558, 9829908, 17498081, 20028422) meeting PS4_Very strong. There are additional probands with the variant reported in the EAHAD database, recorded from the literature. The variant is absent from gnomAD v2.1.1 and v3, which meets PM2_Supporting. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PVS1, PS4, PM2_Supporting.
Met criteria codes
PS4
6 patients with severe (PMID: 22103590, 20102490, 8307558, 9829908, 17498081) and 1 patient with moderate (20028422) hemophilia A are reported with the 4-bp deletion leading to the frameshift variant, Ile1374ThrfsTer49 in the literature and meet F8-phenotype criteria. PS4 is applied.
PVS1
The variant is a 4-bp deletion that results in a frameshift, Ile1374ThrfsTer49, with termination occurring in exon 14/26, expected to cause NMD.
PM2_Supporting
The c.4121_4124del (p.Ile1374fs) variant is completely absent in population databases (gnomAD v2.1.1/gnomAD v3).
Curation History
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