X-154961120-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000132.4(F8):c.1492G>A(p.Gly498Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000184 in 1,089,685 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 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
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
F8 | ENST00000360256.9 | c.1492G>A | p.Gly498Arg | missense_variant | Exon 10 of 26 | 1 | NM_000132.4 | ENSP00000353393.4 | ||
F8 | ENST00000647125.1 | n.*1368G>A | non_coding_transcript_exon_variant | Exon 11 of 14 | ENSP00000496062.1 | |||||
F8 | ENST00000647125.1 | n.*1368G>A | 3_prime_UTR_variant | Exon 11 of 14 | ENSP00000496062.1 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 0AN: 111499Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 33743 FAILED QC
GnomAD4 exome AF: 0.00000184 AC: 2AN: 1089685Hom.: 0 Cov.: 27 AF XY: 0.00000281 AC XY: 1AN XY: 355633
GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 111499Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 33743
ClinVar
Submissions by phenotype
Hereditary factor VIII deficiency disease Pathogenic:2
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The F8 c.1492G>A; p.Gly498Arg variant (rs137852414), also known as Gly479Arg, is reported in the literature in several individuals affected with hemophilia A, with a severity ranging from mild to severe (see F8 variant database and references therein). This variant is reported in ClinVar (Variation ID: 10217), but is absent from the general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at residue 498 is highly conserved, and computational algorithms (SIFT, PolyPhen-2) predict that this is deleterious. Based on available information, this variant is considered to be pathogenic. References: Link to F8 variant database for p.Gly498Arg: http://www.factorviii-db.org/advance_search_results.php?dosearch=1&nucleotide=1492 -
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