chr3-93877155-G-C

Position:

• chr3-93877155-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000313.4(PROS1):​c.1681C>G​(p.Arg561Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PROS1 NM_000313.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 1.04

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROS1	NM_000313.4	c.1681C>G	p.Arg561Gly	missense_variant	14/15	ENST00000394236.9	NP_000304.2
PROS1	NM_001314077.2	c.1777C>G	p.Arg593Gly	missense_variant	15/16		NP_001301006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROS1	ENST00000394236.9	c.1681C>G	p.Arg561Gly	missense_variant	14/15	1	NM_000313.4	ENSP00000377783.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1999

- -

Protein S deficiency disease Uncertain:1

Uncertain significance, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D;.;.;D;.
Eigen	Benign	-0.057
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.74	.;T;T;T;T
M_CAP	Benign	0.054	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.3	M;.;.;M;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.1	N;.;.;.;.
REVEL	Uncertain	0.51
Sift	Benign	0.16	T;.;.;.;.
Sift4G	Benign	0.11	T;.;.;.;.
Polyphen		0.85	P;.;.;P;.
Vest4		0.63
MutPred		0.89		Loss of sheet (P = 0.0037);.;.;Loss of sheet (P = 0.0037);.;
MVP		0.87
MPC		0.68
ClinPred		0.66	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.82

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: rs121918476; hg19: chr3-93595999;