rs6122
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_000313.4(PROS1):c.233C>T(p.Thr78Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000676 in 1,612,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T78T) has been classified as Uncertain significance.
Frequency
Consequence
NM_000313.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PROS1 | NM_000313.4 | c.233C>T | p.Thr78Met | missense_variant, splice_region_variant | 2/15 | ENST00000394236.9 | |
PROS1 | NM_001314077.2 | c.329C>T | p.Thr110Met | missense_variant, splice_region_variant | 3/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PROS1 | ENST00000394236.9 | c.233C>T | p.Thr78Met | missense_variant, splice_region_variant | 2/15 | 1 | NM_000313.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152114Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251352Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135858
GnomAD4 exome AF: 0.0000712 AC: 104AN: 1459970Hom.: 0 Cov.: 31 AF XY: 0.0000620 AC XY: 45AN XY: 726284
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152232Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74436
ClinVar
Submissions by phenotype
PROS1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 26, 2024 | The PROS1 c.233C>T variant is predicted to result in the amino acid substitution p.Thr78Met. This variant, previously described as p.Thr37Met using legacy nomenclature, has been reported in multiple individuals with protein S deficiency (Gandrille et al. 1995. PubMed ID: 7803790; Alhenc-Gelas et al. 2010. PubMed ID: 20880255). Some carriers of this variant were reported to be unaffected or have a mild reduction in the activity of protein S (Alhenc-Gelas et al. 2010. PubMed ID: 20880255; Rezende et al. 2002. PubMed ID: 12351389). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 27, 2022 | - - |
Thrombophilia due to protein S deficiency, autosomal recessive Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 04, 2023 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 78 of the PROS1 protein (p.Thr78Met). This variant is present in population databases (rs6122, gnomAD 0.006%). This missense change has been observed in individuals with PROS1-related conditions (PMID: 7803790, 12351389, 20880255, 22261441, 32964666). This variant is also known as p.Thr37Met. ClinVar contains an entry for this variant (Variation ID: 215991). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PROS1 function (PMID: 12351389). For these reasons, this variant has been classified as Pathogenic. - |
Protein S deficiency disease Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Feb 01, 2019 | - - |
Deep venous thrombosis Uncertain:1
Uncertain significance, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Feb 01, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at