dbSNP rs41267007: PROS1:p.Arg233Lys (chr3-93900833-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6BS1BS2

The NM_000313.4(PROS1):c.698G>A(p.Arg233Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00528 in 1,613,702 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.0031 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0055 ( 133 hom. )

Consequence

PROS1
NM_000313.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: -0.162

Publications

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

PROS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 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, 10 uncertain in NM_000313.4

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, hereditary thrombophilia due to congenital protein S deficiency, thrombophilia due to protein S deficiency, autosomal recessive, protein S deficiency.

BP4

Computational evidence support a benign effect (MetaRNN=0.0106553435).

BP6

Variant 3-93900833-C-T is Benign according to our data. Variant chr3-93900833-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 161346.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00307 (468/152372) while in subpopulation SAS AF = 0.0366 (177/4830). AF 95% confidence interval is 0.0322. There are 2 homozygotes in GnomAd4. There are 264 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROS1	NM_000313.4	MANE Select	c.698G>A	p.Arg233Lys	missense	Exon 7 of 15	NP_000304.2	A0A0S2Z4K3
	PROS1	NM_001314077.2		c.794G>A	p.Arg265Lys	missense	Exon 8 of 16	NP_001301006.1	A0A0S2Z4L3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PROS1	ENST00000394236.9	TSL:1 MANE Select	c.698G>A	p.Arg233Lys	missense	Exon 7 of 15	ENSP00000377783.3	P07225
PROS1	ENST00000407433.6	TSL:1	c.653G>A	p.Arg218Lys	missense	Exon 7 of 15	ENSP00000385794.2	G5E9F8
PROS1	ENST00000650591.1		c.794G>A	p.Arg265Lys	missense	Exon 8 of 16	ENSP00000497376.1	A0A0S2Z4L3

Frequencies

GnomAD3 genomes

AF:

0.00309

AC:

470

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0368

Gnomad FIN

AF:

0.00216

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00322

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00644

AC:

1618

AN:

251296

AF XY:

0.00811

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00228

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00213

Gnomad NFE exome

AF:

0.00368

Gnomad OTH exome

AF:

0.00815

GnomAD4 exome

AF:

0.00551

AC:

8055

AN:

1461330

Hom.:

133

Cov.:

AF XY:

0.00637

AC XY:

4633

AN XY:

726978

show subpopulations

African (AFR)

AF:

0.000388

AC:

AN:

33470

American (AMR)

AF:

0.00253

AC:

113

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00165

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39692

South Asian (SAS)

AF:

0.0338

AC:

2915

AN:

86238

European-Finnish (FIN)

AF:

0.00227

AC:

121

AN:

53364

Middle Eastern (MID)

AF:

0.0184

AC:

101

AN:

5490

European-Non Finnish (NFE)

AF:

0.00396

AC:

4407

AN:

1111886

Other (OTH)

AF:

0.00563

AC:

340

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

450

899

1349

1798

2248

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

200

400

600

800

1000

<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:

0.00307

AC:

468

AN:

152372

Hom.:

Cov.:

AF XY:

0.00354

AC XY:

264

AN XY:

74516

show subpopulations

African (AFR)

AF:

0.000577

AC:

AN:

41594

American (AMR)

AF:

0.00137

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.0366

AC:

177

AN:

4830

European-Finnish (FIN)

AF:

0.00216

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00322

AC:

219

AN:

68038

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

103

129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00314

Hom.:

Bravo

AF:

0.00220

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.00738

AC:

896

Asia WGS

AF:

0.00895

AC:

AN:

3478

EpiCase

AF:

0.00436

EpiControl

AF:

0.00373

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Thrombophilia due to protein S deficiency, autosomal dominant (2)

Finnish congenital nephrotic syndrome (1)

PROS1-related disorder (1)

Protein S deficiency disease (1)

Retinal dystrophy (1)

Thrombophilia due to protein S deficiency, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.13

CADD

Benign

9.0

(source)

DANN

Benign

0.72

DEOGEN2

Uncertain

0.51

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.092

LIST_S2

Benign

0.67

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.58

PhyloP100

-0.16

PrimateAI

Benign

0.25

PROVEAN

Benign

0.13

REVEL

Uncertain

0.50

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.094

MVP

0.68

MPC

0.23

ClinPred

0.0027

GERP RS

-0.33

Varity_R

0.23

gMVP

0.37

Mutation Taster

=91/9

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

Computational scores

Splicing

Publications

Other links and lift over