rs137852413
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_000132.4(F8):c.1481T>G(p.Ile494Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I494T) has been classified as Pathogenic.
Frequency
Consequence
NM_000132.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
F8 | NM_000132.4 | c.1481T>G | p.Ile494Ser | missense_variant | 10/26 | ENST00000360256.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
F8 | ENST00000360256.9 | c.1481T>G | p.Ile494Ser | missense_variant | 10/26 | 1 | NM_000132.4 | P1 | |
F8 | ENST00000647125.1 | c.*1357T>G | 3_prime_UTR_variant, NMD_transcript_variant | 11/14 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD4 exome Cov.: 27
GnomAD4 genome Cov.: 22
ClinVar
Submissions by phenotype
Hereditary factor VIII deficiency disease Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 23, 2021 | The F8 c.1481T>G; p.Ile494Ser variant is reported in the literature in at least one individual affected with moderate to severe hemophilia A (see F8 database and references therein). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, another variant at this codon (c.1481T>C, p.Ile494Thr) has been reported in individuals with mild hemophilia A and is considered pathogenic (Schwaab 1995). The isoleucine at codon 494 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.983). Based on available information, this variant is considered to be likely pathogenic. References: Link to Factor VIII database: https://f8-db.eahad.org/index.php Johnsen JM et al. Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative. Blood Adv. 2017 May 18;1(13):824-834. PMID: 29296726. Schwaab R et al. Characterization of mutations within the factor VIII gene of 73 unrelated mild and moderate haemophiliacs. Br J Haematol. 1995 Oct;91(2):458-64. PMID: 8547094. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.