rs387906429
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_000132.4(F8):c.601+1632G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 112,151 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_000132.4 intron
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.601+1632G>A | intron_variant | Intron 4 of 25 | 1 | NM_000132.4 | ENSP00000353393.4 | |||
F8 | ENST00000423959.5 | c.496+1632G>A | intron_variant | Intron 4 of 5 | 3 | ENSP00000409446.1 | ||||
F8 | ENST00000647125.1 | n.*387+1632G>A | intron_variant | Intron 4 of 13 | ENSP00000496062.1 |
Frequencies
GnomAD3 genomes AF: 0.0000178 AC: 2AN: 112151Hom.: 0 Cov.: 23 AF XY: 0.0000292 AC XY: 1AN XY: 34303
GnomAD4 genome AF: 0.0000178 AC: 2AN: 112151Hom.: 0 Cov.: 23 AF XY: 0.0000292 AC XY: 1AN XY: 34303
ClinVar
Submissions by phenotype
Hereditary factor VIII deficiency disease Pathogenic:1
- -
F8-related disorder Uncertain:1
The F8 c.601+1632G>A variant is predicted to interfere with splicing. This variant has been reported in the hemizygous state in two male siblings with mild Hemophilia A and in the heterozygous state in their mother with unknown phenotype (Youssoufian et al. 1988. PubMed ID: 2838411). Functional study and Alamut evaluation showed that this variant leads to a defect in RNA processing and reduces F8 protein levels (Youssoufian et al. 1988. PubMed ID: 2838411; Zimmermann et al. 2012. PubMed ID: 23088352). This variant is reported in 1 (hemizygous) of 13922 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/X-154219579-C-T). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at