rs387906674

chr3-93893025-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000313.4(PROS1):c.1063C>T(p.Arg355Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R355H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PROS1 NM_000313.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.48

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 Pathogenic. Variant got 16 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, 5 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 chr3-93893024-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 956390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93
• PP5: Variant 3-93893025-G-A is Pathogenic according to our data. Variant chr3-93893025-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 29846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-93893025-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROS1	NM_000313.4	c.1063C>T	p.Arg355Cys	missense_variant	10/15	ENST00000394236.9
PROS1	NM_001314077.2	c.1159C>T	p.Arg387Cys	missense_variant	11/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROS1	ENST00000394236.9	c.1063C>T	p.Arg355Cys	missense_variant	10/15	1	NM_000313.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251384 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135884

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461544 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727108

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PROS1 related disorder (ClinVar ID: VCV000029846, PMID:21172841). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000956390, PMID:15238143). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.826>=0.6). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000199). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 14, 2010	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 23, 2021

This variant is present in population databases (rs387906674, ExAC 0.05%). This sequence change replaces arginine with cysteine at codon 355 of the PROS1 protein (p.Arg355Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant has been observed in individual(s) with protein S deficiency (PMID: 29748776, 21764702, 27667277, 21172841, 21486865, 27748013). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg314Cys in the literature. ClinVar contains an entry for this variant (Variation ID: 29846). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Arg355 amino acid residue in PROS1. Other variant(s) that disrupt this residue have been observed in individuals with PROS1-related conditions (PMID: 15238143), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;.;.;D;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Pathogenic	3.2	M;.;.;M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-7.2	D;.;.;.;.;.
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;.;.;.;.;.
Sift4G	Pathogenic	0.0010	D;.;.;.;.;.
Polyphen		1.0	D;.;.;D;.;.
Vest4		0.97
MutPred		0.72		Gain of methylation at K358 (P = 0.0566);.;.;Gain of methylation at K358 (P = 0.0566);Gain of methylation at K358 (P = 0.0566);.;
MVP		0.93
MPC		0.99
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.68
gMVP		0.84

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: rs387906674; hg19: chr3-93611869; COSMIC: COSV67774997;