rs137852436
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong
The NM_000132.4(F8):c.2167G>A(p.Ala723Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000273 in 1,097,863 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000132.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
F8 | ENST00000360256.9 | c.2167G>A | p.Ala723Thr | missense_variant | Exon 14 of 26 | 1 | NM_000132.4 | ENSP00000353393.4 | ||
F8 | ENST00000647125.1 | n.*1833G>A | non_coding_transcript_exon_variant | Exon 14 of 14 | ENSP00000496062.1 | |||||
F8 | ENST00000647125.1 | n.*1833G>A | 3_prime_UTR_variant | Exon 14 of 14 | ENSP00000496062.1 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD3 exomes AF: 0.00000550 AC: 1AN: 181821Hom.: 0 AF XY: 0.0000149 AC XY: 1AN XY: 67031
GnomAD4 exome AF: 0.00000273 AC: 3AN: 1097863Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 2AN XY: 363295
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
Hereditary factor VIII deficiency disease Pathogenic:4
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Variant summary: F8 c.2167G>A (p.Ala723Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five 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 181821 control chromosomes. c.2167G>A has been reported in the literature in multiple individuals affected with mild/moderate Hemophilia A (example: Cygan_2016). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 27704658). ClinVar contains an entry for this variant (Variation ID: 10246). Based on the evidence outlined above, the variant was classified as pathogenic. -
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.63). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000010246 / PMID: 1908096). A different missense change at the same codon (p.Ala723Val) has been reported to be associated with F8 related disorder (PMID: 25854144). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
The F8 c.2167G>A (p.Ala723Thr) variant, which was also previously referred to as p.Ala704Thr, is a missense variant. Across a selection of the available literature, it has been identified in at least four unrelated individuals with mild-to-moderate hemophilia A (Higuchi et al. 1991; Antonarakis et al. 1995; Inaba et al. 2013). For three cases, factor VIII activity was reported as falling within 2-29%. In the fourth case, the lowest FVIII:C level was recorded clinically was 0.034 IU/mL. This variant is reported at a frequency of 0.000053 in the South Asian population of the Genome Aggregation Database, where it is found on a single hemizygous allele. Coverage of this genomic region is good, suggesting the variant is rare. In addition, multiple in silico algorithms predict the variant, which is located in the F5/8 type A2 domain, to have a deleterious effect. Based on this evidence and application of the ACMG criteria, the p.Ala723Thr variant is classified as pathogenic for hemophilia A, FVIII deficiency. -
not provided Pathogenic:3
PP1_strong, PP3, PM1, PM2, PM6, PS4_moderate -
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22883072, 31064749, 27380589, 19473423, 27704658, 18691168, 8547094, 15625837, 11857744, 16972227, 24845853, 23625609, 21645180, 23711237, 11179760, 20331761, 23617593, 32224444, 25550078, 1908096, 9452104, 15921397, 29296726, 33245802, 33706050, 32897612) -
The F8 c.2167G>A; p.Ala723Thr variant (rs137852436), also known as Ala704Thr, has been reported in multiple individuals diagnosed with mild to moderate hemophilia A (see link to FVIII database and references therein, Higuchi 1991, Markoff 2009). The variant is reported in the ClinVar database (Variation ID: 10246) and is observed on only 1 allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at codon 723 is highly conserved, and additional variants at this position (c.2168C>A; p.Ala723Asp and c.2168C>T; p.Ala723Val) have been described in individuals with hemophilia A and are considered pathogenic (see link to FVIII database and references therein). Based on available information, the p.Ala723Thr variant is considered pathogenic. References: Link to Factor VIII variant database: http://www.factorviii-db.org/ Higuchi M et al. Molecular characterization of severe hemophilia A suggests that about half the mutations are not within the coding regions and splice junctions of the factor VIII gene. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7405-9. Markoff A et al. Combined homology modelling and evolutionary significance evaluation of missense mutations in blood clotting factor VIII to highlight aspects of structure and function. Haemophilia. 2009 Jul;15(4):932-41. -
Hereditary factor VIII deficiency disease;C5676879:Thrombophilia, X-linked, due to factor 8 defect Pathogenic:1
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Hereditary factor IX deficiency disease Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at