rs121918474

Positions:

chr3-93905799-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 10P and 2B. PM1PP5_Very_StrongBP4BS2_Supporting

The NM_000313.4(PROS1):c.586A>G(p.Lys196Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,612,018 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 3 hom. )

Consequence

PROS1
NM_000313.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 1.76

Variant links:

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]

PROS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a domain EGF-like 2; calcium-binding (size 43) in uniprot entity PROS_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000313.4

PP5

Variant 3-93905799-T-C is Pathogenic according to our data. Variant chr3-93905799-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 13318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.10928759). . Strength limited to SUPPORTING due to the PP5.

BS2

High Homozygotes in GnomAdExome4 at 3 SD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROS1	NM_000313.4 linkuse as main transcript	c.586A>G	p.Lys196Glu	missense_variant	6/15	ENST00000394236.9	NP_000304.2
PROS1	NM_001314077.2 linkuse as main transcript	c.682A>G	p.Lys228Glu	missense_variant	7/16		NP_001301006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROS1	ENST00000394236.9 linkuse as main transcript	c.586A>G	p.Lys196Glu	missense_variant	6/15	1	NM_000313.4	ENSP00000377783	P1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

250848

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135644

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000157

AC:

229

AN:

1459682

Hom.:

Cov.:

AF XY:

0.000172

AC XY:

125

AN XY:

726346

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00575

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00135

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Thrombophilia due to protein S deficiency, autosomal dominant

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 1994	- -
Pathogenic, criteria provided, single submitter	research	Snyder Lab, Genetics Department, Stanford University	Jan 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The PROS1 c.586A>G (p.Lys196Glu) missense variant, commonly referred to as the protein S Tokushima variant, is well described in the literature and only found in the Japanese population, where it has been shown to account for between nine and 30 percent of protein S abnormalities (Huang et al. 2016). Across a selection of the literature that studied 488 cases with protein S deficiency and thrombotic disease, the p.Lys196Glu variant is reported in a homozygous state in four affected individuals, in a compound heterozygous state in two affected individuals and one unaffected relative, and in a heterozygous state in 39 affected individuals, all of whom exhibited reduced protein S activity (Hayashi et al. 1994; Kimura et al. 2006a; Kimura et al. 2006b; Miyata et al. 2009; Yamanouchi et al. 2009; Ikejiri et al. 2010; Hayakawa et al. 2011). The p.Lys196Glu variant was detected in 103 out of 5751 controls and is reported at a frequency of 0.00046 in the East Asian population of the Exome Aggregation Consortium. Ikejiri et al. (2010) report the frequency of the variant is significantly higher in individuals with protein S deficiency and thrombotic disease compared to healthy individuals with odds ratios ranging from 4.99 to 8.56 for individuals being treated with warfarin in whom thrombotic disease has been resolved and individuals with thrombotic disease, respectively. Protein S activity in individuals carrying the p.Lys196Glu in a heterozygous state can range from being only slightly reduced to being nearly normal (Hayakawa et al. 2010). Banno et al. (2015) constructed a mouse model of the variant and demonstrated decreased protein C cofactor activity and increased susceptibility to venous thrombosis compared to wild type. Based on the collective evidence the p.Lys196Glu variant is classified as pathogenic for protein S deficiency and is considered to be a risk factor for thrombotic disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

PROS1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 30, 2024

The PROS1 c.586A>G variant is predicted to result in the amino acid substitution p.Lys196Glu. This variant is alternatively referred to as p.Lys155Glu using legacy nomenclature. This variant was reported in individuals with protein S deficiency and deep vein thrombosis (Hayashi et al. 1994. PubMed ID: 8298131; Miyata et al. 2008. PubMed ID: 18954896; Ikejiri et al. 2010. PubMed ID: 20811787). This variant is reported in 0.038% of alleles in individuals of East Asian descent in gnomAD. In vitro and In vivo experimental studies suggest this variant impacts protein function (Banno et al. 2015. PubMed ID: 26251307; Miyata et al. 2008. PubMed ID: 18954896). This variant is interpreted as pathogenic. -

Thrombophilia due to protein S deficiency, autosomal recessive

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 03, 2023

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 196 of the PROS1 protein (p.Lys196Glu). This variant is present in population databases (rs121918474, gnomAD 0.03%). This missense change has been observed in individuals with conditions associated with reduce protein S deficiency including venous thromboembolism (VTE). Case-control studies have demonstrated that this is a common variant that is associated with increased risk of VTE in Japanese populations, though measurable protein S activity is not always reduced in these individuals and not all carriers are clinically affected (PMID: 10811787, 15978566, 16461766, 24233386, 27660039). This variant is also known as p.Lys155Glu and S-Tokushima. ClinVar contains an entry for this variant (Variation ID: 13318). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PROS1 protein function. Experimental studies have shown that this missense change affects PROS1 function (PMID: 16961608, 26251307, 30349894). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Uncertain

0.016

BayesDel_noAF

Uncertain

0.090

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.56

D;.;.;D;.

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.63

.;T;T;T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.11

T;T;T;T;T

MetaSVM

Uncertain

-0.099

MutationAssessor

Benign

1.3

L;.;.;L;.

MutationTaster

Benign

0.75

A;A

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.83

N;.;.;.;.

REVEL

Uncertain

0.56

Sift

Benign

0.37

T;.;.;.;.

Sift4G

Benign

0.70

T;.;.;.;.

Polyphen

0.0010

B;.;.;B;.

Vest4

0.39

MVP

0.82

MPC

0.32

ClinPred

0.035

GERP RS

0.60

Varity_R

0.20

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over