rs137852406
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000132.4(F8):āc.940A>Gā(p.Thr314Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000182 in 1,098,046 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T314N) has been classified as Uncertain significance.
Frequency
Consequence
NM_000132.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
F8 | NM_000132.4 | c.940A>G | p.Thr314Ala | missense_variant | 7/26 | ENST00000360256.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
F8 | ENST00000360256.9 | c.940A>G | p.Thr314Ala | missense_variant | 7/26 | 1 | NM_000132.4 | P1 | |
F8 | ENST00000647125.1 | c.*816A>G | 3_prime_UTR_variant, NMD_transcript_variant | 8/14 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 exomes AF: 0.00000545 AC: 1AN: 183340Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 67808
GnomAD4 exome AF: 0.00000182 AC: 2AN: 1098046Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 1AN XY: 363440
GnomAD4 genome ? Cov.: 23
ClinVar
Submissions by phenotype
Hereditary factor VIII deficiency disease Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 20, 2024 | Variant summary: F8 c.940A>G (p.Thr314Ala) 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 183340 control chromosomes (gnomAD). c.940A>G has been reported in the literature in multiple individuals affected with Factor VIII Deficiency (Hemophilia A; e.g. Higughi_1991b, Schwaab_1995, Eckhardt_2013). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 1924291, 8547094, 23926300). ClinVar contains an entry for this variant (Variation ID: 10197). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1991 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | F8: PM1, PM2, PS4:Moderate - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at