rs144526169

chr3-93910681-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000313.4(PROS1):c.284G>A(p.Gly95Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00057 in 1,613,280 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G95R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (1 hom.)
• Consequence: PROS1 NM_000313.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:5
• Conservation: PhyloP100: 1.66

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000313.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROS1	NM_000313.4	c.284G>A	p.Gly95Glu	missense_variant	4/15	ENST00000394236.9
PROS1	NM_001314077.2	c.380G>A	p.Gly127Glu	missense_variant	5/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROS1	ENST00000394236.9	c.284G>A	p.Gly95Glu	missense_variant	4/15	1	NM_000313.4	P1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152020 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000335 AC: 84 AN: 250584 Hom.: 0 AF XY: 0.000362 AC XY: 49 AN XY: 135418

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000592

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000589 AC: 861 AN: 1461142 Hom.: 1 Cov.: 30 AF XY: 0.000585 AC XY: 425 AN XY: 726830

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000733

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000388 AC: 59 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74370

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000364 Hom.: 0

Bravo AF: 0.000468

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000313 AC: 38

EpiCase AF: 0.000436

EpiControl AF: 0.000475

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Protein S deficiency disease Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -

Thrombophilia due to protein S deficiency, autosomal dominant Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The PROS1 c.284G>A (p.Gly95Glu) missense variant, also known as p.Gly54Glu, has been identified in a heterozygous state in three unrelated affected individuals with protein S deficiency. It has also been detected in a family member where disease status is not confirmed (Simmonds et al. 1996; Alhenc-Gelas et al 2010). Control data are unavailable for this variant, and it has been reported at a frequency of 0.00057 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the available evidence, the p.Gly95Glu variant is classified as a variant of unknown significance but suspicious for pathogenicity for protein S deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -

Thrombocytopenia;C1458140:Abnormal bleeding Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Birmingham Platelet Group; University of Birmingham

May 01, 2020

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2016

- -

Thrombophilia due to protein S deficiency, autosomal recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 27, 2022

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 95 of the PROS1 protein (p.Gly95Glu). This variant is present in population databases (rs144526169, gnomAD 0.06%). This missense change has been observed in individual(s) with protein S deficiency (PMID: 8943854, 20880255). This variant is also known as 430G>A and Gly54Glu. ClinVar contains an entry for this variant (Variation ID: 161354). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.73	D;.;.;D;.;.
Eigen	Benign	0.0061
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.59	D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	1.1	L;.;.;L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.7	D;.;.;.;.;.
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0090	D;.;.;.;.;.
Sift4G	Uncertain	0.021	D;.;.;.;.;.
Polyphen		0.98	D;.;.;D;.;.
Vest4		0.42
MVP		0.97
MPC		0.70
ClinPred		0.11	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.91

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

Other links and lift over

dbSNP: rs144526169; hg19: chr3-93629525; COSMIC: COSV62399812;