chrX-155022432-C-A
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PP5BP4BS2
The NM_000132.4(F8):c.121G>T(p.Gly41Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000405 in 1,208,566 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G41S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000132.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
F8 | ENST00000360256.9 | c.121G>T | p.Gly41Cys | missense_variant | Exon 1 of 26 | 1 | NM_000132.4 | ENSP00000353393.4 | ||
F8 | ENST00000453950.1 | c.103G>T | p.Gly35Cys | missense_variant | Exon 2 of 5 | 3 | ENSP00000389153.1 | |||
F8 | ENST00000423959.5 | c.38+4348G>T | intron_variant | Intron 1 of 5 | 3 | ENSP00000409446.1 | ||||
F8 | ENST00000647125.1 | n.121G>T | splice_region_variant, non_coding_transcript_exon_variant | Exon 1 of 14 | ENSP00000496062.1 |
Frequencies
GnomAD3 genomes AF: 0.0000451 AC: 5AN: 110913Hom.: 0 Cov.: 23 AF XY: 0.0000302 AC XY: 1AN XY: 33097
GnomAD3 exomes AF: 0.000115 AC: 21AN: 182769Hom.: 0 AF XY: 0.000134 AC XY: 9AN XY: 67283
GnomAD4 exome AF: 0.0000401 AC: 44AN: 1097653Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 15AN XY: 363109
GnomAD4 genome AF: 0.0000451 AC: 5AN: 110913Hom.: 0 Cov.: 23 AF XY: 0.0000302 AC XY: 1AN XY: 33097
ClinVar
Submissions by phenotype
Hereditary factor VIII deficiency disease Pathogenic:1
- -
Thrombophilia, X-linked, due to factor 8 defect Pathogenic:1
- -
not specified Uncertain:1
Variant summary: F8 c.121G>T (p.Gly41Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 182769 control chromosomes, including 9 hemizygotes. This frequency is not significantly higher than estimated for a pathogenic variant in F8 causing Factor VIII Deficiency (Hemophilia A) (0.00011 vs 0.0098), allowing no conclusion about variant significance. c.121G>T has been reported in the literature in individuals with Factor VIII Deficiency (Hemophilia A) with variable severity, ranging from mild to severe (example: Preisler_2021, Hallden_2012, Tuddenham_1994). It has also been reported in at-least one individual with repeat normal FVIII levels (example: Andersson_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32100410, 23020595, 33477601, 7984443). ClinVar contains an entry for this variant (Variation ID: 10156). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at