rs368074804
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate
The NM_000313.4(PROS1):c.728-1G>T variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000000685 in 1,459,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Consequence
NM_000313.4 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PROS1 | NM_000313.4 | c.728-1G>T | splice_acceptor_variant, intron_variant | Intron 7 of 14 | ENST00000394236.9 | NP_000304.2 | ||
PROS1 | NM_001314077.2 | c.824-1G>T | splice_acceptor_variant, intron_variant | Intron 8 of 15 | NP_001301006.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250920Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135602
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459916Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726278
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Thrombophilia due to protein S deficiency, autosomal recessive Pathogenic:1
This variant is present in population databases (rs368074804, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PROS1-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change affects an acceptor splice site in intron 7 of the PROS1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PROS1 are known to be pathogenic (PMID: 9241758). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at