rs28935203
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_000132.4(F8):c.5096A>T(p.Tyr1699Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000912 in 1,096,156 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1699S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000132.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
F8 | NM_000132.4 | c.5096A>T | p.Tyr1699Phe | missense_variant | 14/26 | ENST00000360256.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
F8 | ENST00000360256.9 | c.5096A>T | p.Tyr1699Phe | missense_variant | 14/26 | 1 | NM_000132.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 exomes AF: 0.00000554 AC: 1AN: 180470Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 65214
GnomAD4 exome AF: 9.12e-7 AC: 1AN: 1096156Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 361732
GnomAD4 genome ? Cov.: 23
ClinVar
Submissions by phenotype
Hereditary factor VIII deficiency disease Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 19, 2023 | Variant summary: F8 c.5096A>T (p.Tyr1699Phe) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 180470 control chromosomes. c.5096A>T has been reported in the literature in multiple individuals affected with Factor VIII Deficiency (Hemophilia A). These data indicate that the variant is very likely to be associated with disease. The following publication have been ascertained in the context of this evaluation (PMID: 23926300). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1990 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota | Dec 31, 2020 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 25, 2023 | The F8 c.5096A>T; p.Tyr1699Phe variant (rs28935203), also known as Tyr1680Phe, is reported in the literature in multiple individuals affected with mild to moderate hemophilia A (see link to FVIII database and references therein). This variant is reported in ClinVar (Variation ID: 10115), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. tyrosine at codon 1699 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.779). Based on available information, the p.Tyr1699Phe variant is considered to be pathogenic. References: Link to variant in FVIII variant database: http://www.factorviii-db.org/ - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 28, 2022 | Published functional studies demonstrate a damaging effect (Pezeshkpoor et al., 2019; van den Biggelaar et al., 2011); Also known as (p.Y1680F); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19473423, 24108539, 10368977, 1554716, 1898735, 21940821, 11857744, 8547094, 17958741, 30997536, 27378673, 33552050, 32791533, 32232366, 24452774, 21909383, 2105906, 18691168, 19302446, 33314404, 27629384, 32299908, 1908096) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at