rs863224838
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000313.4(PROS1):c.967delTinsGG(p.Phe323fs) variant causes a frameshift, missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
PROS1
NM_000313.4 frameshift, missense, splice_region
NM_000313.4 frameshift, missense, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.56
Genes affected
PROS1 (HGNC:9456): (protein S) This gene encodes a vitamin K-dependent plasma protein that functions as a cofactor for the anticoagulant protease, activated protein C (APC) to inhibit blood coagulation. It is found in plasma in both a free, functionally active form and also in an inactive form complexed with C4b-binding protein. Mutations in this gene result in autosomal dominant hereditary thrombophilia. An inactive pseudogene of this locus is located at an adjacent region on chromosome 3. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar processing to generate mature protein. [provided by RefSeq, Oct 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-93893121-A-CC is Pathogenic according to our data. Variant chr3-93893121-A-CC is described in ClinVar as [Pathogenic]. Clinvar id is 216868.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PROS1 | NM_000313.4 | c.967delTinsGG | p.Phe323fs | frameshift_variant, missense_variant, splice_region_variant | 10/15 | ENST00000394236.9 | NP_000304.2 | |
PROS1 | NM_001314077.2 | c.1063delTinsGG | p.Phe355fs | frameshift_variant, missense_variant, splice_region_variant | 11/16 | NP_001301006.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PROS1 | ENST00000394236.9 | c.967delTinsGG | p.Phe323fs | frameshift_variant, missense_variant, splice_region_variant | 10/15 | 1 | NM_000313.4 | ENSP00000377783.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Thrombophilia due to protein S deficiency, autosomal recessive Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 23, 2018 | For these reasons, this variant has been classified as Pathogenic. Truncating variants in PROS1 are known to be pathogenic. This particular truncation has been reported in the literature in patients affected with protein S deficiency and venous thromboembolism (PMID: 16885060, 18435454, 24014240). This variant segregated with protein S deficiency in several families. This change is also known as c.1113T>GG in the literature. This sequence change deletes 1 nucleotide and inserts 2 nucleotides in exon 10 of the PROS1 mRNA (c.967delTinsGG), causing a frameshift at codon 323. This creates a premature translational stop signal (p.Phe323Glyfs*6) and is expected to result in an absent or disrupted protein product. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at