Genetic Variant NM_000313.4:c.431C>A (chr3-93906059-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_000313.4(PROS1):c.431C>A(p.Thr144Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000631 in 1,614,106 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00065 ( 4 hom. )

Consequence

PROS1
NM_000313.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 2.26

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

thrombophilia due to protein S deficiency, autosomal dominant
Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
hereditary thrombophilia due to congenital protein S deficiency
Inheritance: AR, SD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
thrombophilia due to protein S deficiency, autosomal recessive
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics

PROS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 34 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.58456 (below the threshold of 3.09). Trascript score misZ: 1.9528 (below the threshold of 3.09). GenCC associations: The gene is linked to thrombophilia due to protein S deficiency, autosomal dominant, thrombophilia due to protein S deficiency, autosomal recessive, hereditary thrombophilia due to congenital protein S deficiency.

BP4

Computational evidence support a benign effect (MetaRNN=0.024283767).

BP6

Variant 3-93906059-G-T is Benign according to our data. Variant chr3-93906059-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 161347.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000447 (68/152260) while in subpopulation SAS AF = 0.00373 (18/4824). AF 95% confidence interval is 0.00241. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000313.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROS1	NM_000313.4	MANE Select	c.431C>A	p.Thr144Asn	missense	Exon 5 of 15	NP_000304.2
	PROS1	NM_001314077.2		c.527C>A	p.Thr176Asn	missense	Exon 6 of 16	NP_001301006.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PROS1	ENST00000394236.9	TSL:1 MANE Select	c.431C>A	p.Thr144Asn	missense	Exon 5 of 15	ENSP00000377783.3
PROS1	ENST00000407433.6	TSL:1	c.431C>A	p.Thr144Asn	missense	Exon 5 of 15	ENSP00000385794.2
PROS1	ENST00000650591.1		c.527C>A	p.Thr176Asn	missense	Exon 6 of 16	ENSP00000497376.1

Frequencies

GnomAD3 genomes

AF:

0.000460

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000514

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000768

AC:

193

AN:

251464

AF XY:

0.000979

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000738

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000650

AC:

950

AN:

1461846

Hom.:

Cov.:

AF XY:

0.000714

AC XY:

519

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.000268

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000421

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00298

AC:

257

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00329

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000539

AC:

599

AN:

1111994

Other (OTH)

AF:

0.000811

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

110

165

220

275

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000447

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41552

American (AMR)

AF:

0.000196

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00373

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000500

AC:

AN:

68024

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000627

Hom.:

Bravo

AF:

0.000348

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000758

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000655

EpiControl

AF:

0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Thrombophilia due to protein S deficiency, autosomal dominant

Uncertain:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

Low GERP score may suggest that this variant may belong in a lower pathogenicity class

Retinal dystrophy

Uncertain:1

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PROS1-related disorder

Benign:1

Dec 21, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

not provided

Benign:1

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PROS1: BS2

Thrombophilia due to protein S deficiency, autosomal recessive

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.38

CADD

Benign

9.2

(source)

DANN

Benign

0.75

DEOGEN2

Uncertain

0.60

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.50

M_CAP

Benign

0.022

MetaRNN

Benign

0.024

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.54

PhyloP100

2.3

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.58

REVEL

Benign

0.18

Sift

Benign

0.32

Sift4G

Benign

0.34

Polyphen

0.0

Vest4

0.38

MVP

0.77

MPC

0.26

ClinPred

0.011

GERP RS

0.13

Varity_R

0.12

gMVP

0.67

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over