rs6123

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000313.4(PROS1):c.2001A>G(p.Pro667Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 1,613,070 control chromosomes in the GnomAD database, including 136,808 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 10408 hom., cov: 32)

Exomes 𝑓: 0.41 ( 126400 hom. )

Consequence

PROS1
NM_000313.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.268

Publications

26 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 3-93874275-T-C is Benign according to our data. Variant chr3-93874275-T-C is described in ClinVar as Benign. ClinVar VariationId is 255811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.268 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROS1	NM_000313.4 link	c.2001A>G	p.Pro667Pro	synonymous_variant	Exon 15 of 15	ENST00000394236.9	NP_000304.2	P07225A0A0S2Z4K3
PROS1	NM_001314077.2 link	c.2097A>G	p.Pro699Pro	synonymous_variant	Exon 16 of 16		NP_001301006.1	P07225A0A0S2Z4L3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROS1	ENST00000394236.9 link	c.2001A>G	p.Pro667Pro	synonymous_variant	Exon 15 of 15	1	NM_000313.4	ENSP00000377783.3		P07225

Frequencies

GnomAD3 genomes

AF:

0.349

AC:

52984

AN:

151904

Hom.:

10400

Cov.:

show subpopulations

Gnomad AFR

AF:

0.156

Gnomad AMI

AF:

0.487

Gnomad AMR

AF:

0.440

Gnomad ASJ

AF:

0.320

Gnomad EAS

AF:

0.555

Gnomad SAS

AF:

0.500

Gnomad FIN

AF:

0.430

Gnomad MID

AF:

0.323

Gnomad NFE

AF:

0.406

Gnomad OTH

AF:

0.360

GnomAD2 exomes

AF:

0.427

AC:

107205

AN:

250796

AF XY:

0.433

show subpopulations

Gnomad AFR exome

AF:

0.148

Gnomad AMR exome

AF:

0.491

Gnomad ASJ exome

AF:

0.321

Gnomad EAS exome

AF:

0.560

Gnomad FIN exome

AF:

0.441

Gnomad NFE exome

AF:

0.414

Gnomad OTH exome

AF:

0.404

GnomAD4 exome

AF:

0.411

AC:

600048

AN:

1461048

Hom.:

126400

Cov.:

AF XY:

0.415

AC XY:

301316

AN XY:

726848

show subpopulations

African (AFR)

AF:

0.139

AC:

4651

AN:

33448

American (AMR)

AF:

0.488

AC:

21816

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.323

AC:

8421

AN:

26110

East Asian (EAS)

AF:

0.581

AC:

23012

AN:

39610

South Asian (SAS)

AF:

0.506

AC:

43646

AN:

86234

European-Finnish (FIN)

AF:

0.449

AC:

23960

AN:

53410

Middle Eastern (MID)

AF:

0.381

AC:

2195

AN:

5758

European-Non Finnish (NFE)

AF:

0.404

AC:

448487

AN:

1111436

Other (OTH)

AF:

0.395

AC:

23860

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

20326

40652

60978

81304

101630

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13894

27788

41682

55576

69470

<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:

0.349

AC:

53000

AN:

152022

Hom.:

10408

Cov.:

AF XY:

0.356

AC XY:

26444

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.155

AC:

6447

AN:

41504

American (AMR)

AF:

0.441

AC:

6737

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.320

AC:

1109

AN:

3466

East Asian (EAS)

AF:

0.554

AC:

2871

AN:

5178

South Asian (SAS)

AF:

0.501

AC:

2416

AN:

4824

European-Finnish (FIN)

AF:

0.430

AC:

4537

AN:

10554

Middle Eastern (MID)

AF:

0.333

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.406

AC:

27580

AN:

67910

Other (OTH)

AF:

0.362

AC:

764

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1683

3367

5050

6734

8417

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

528

1056

1584

2112

2640

<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:

0.393

Hom.:

34474

Bravo

AF:

0.340

Asia WGS

AF:

0.489

AC:

1696

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Thrombophilia due to protein S deficiency, autosomal dominant

Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 10494768, 17157360) -

Thrombophilia due to protein S deficiency, autosomal recessive

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

3.7

(source)

DANN

Benign

0.66

PhyloP100

-0.27

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over