3-93886412-G-A

Position:

chr3-93886412-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000313.4(PROS1):c.1247C>T(p.Pro416Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000973 in 1,613,568 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000092 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000098 ( 1 hom. )

Consequence

PROS1
NM_000313.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.46

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_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16730836).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROS1	NM_000313.4 linkuse as main transcript	c.1247C>T	p.Pro416Leu	missense_variant	11/15	ENST00000394236.9	NP_000304.2
PROS1	NM_001314077.2 linkuse as main transcript	c.1343C>T	p.Pro448Leu	missense_variant	12/16		NP_001301006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROS1	ENST00000394236.9 linkuse as main transcript	c.1247C>T	p.Pro416Leu	missense_variant	11/15	1	NM_000313.4	ENSP00000377783	P1

Frequencies

GnomAD3 genomes

AF:

0.0000856

AC:

AN:

151940

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.0000875

AC:

AN:

251354

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000359

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000978

AC:

143

AN:

1461510

Hom.:

Cov.:

AF XY:

0.000111

AC XY:

AN XY:

727070

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.000359

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000926

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000921

AC:

AN:

152058

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.0000688

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Thrombophilia due to protein S deficiency, autosomal dominant;C3281092:Thrombophilia due to protein S deficiency, autosomal recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 26, 2021

- -

Thrombophilia due to protein S deficiency, autosomal recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 02, 2021

This sequence change replaces proline with leucine at codon 416 of the PROS1 protein (p.Pro416Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs565325519, ExAC 0.02%). This missense change has been observed in individual(s) with protein S deficiency (PMID: 26466767). ClinVar contains an entry for this variant (Variation ID: 216419). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

0.093

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.15

DEOGEN2

Uncertain

0.43

T;.;.;T;.;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.43

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.88

.;D;D;D;D;D

M_CAP

Benign

0.0085

MetaRNN

Benign

0.17

T;T;T;T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.2

L;.;.;L;.;.

MutationTaster

Benign

0.99

D;D

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.1

N;.;.;.;.;.

REVEL

Benign

0.21

Sift

Benign

1.0

T;.;.;.;.;.

Sift4G

Benign

1.0

T;.;.;.;.;.

Polyphen

0.015

B;.;.;B;.;.

Vest4

0.18

MutPred

0.82

Loss of disorder (P = 0.0456);.;.;Loss of disorder (P = 0.0456);Loss of disorder (P = 0.0456);.;

MVP

0.75

MPC

0.25

ClinPred

0.041

GERP RS

2.5

Varity_R

0.050

gMVP

0.63

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