3-93879279-C-T

Variant names:

• chr3-93879279-C-T
• rs138925964
• NM_000313.4:c.1528G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BS1 BS2

The NM_000313.4(PROS1):​c.1528G>A​(p.Val510Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00064 in 1,614,028 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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 0.0035 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (1 hom.)
• Consequence: PROS1 NM_000313.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:6 O:1
• Conservation: PhyloP100: -0.0910
• Publications: 5 publications found

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

ACMG classification

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, 5 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, thrombophilia due to protein S deficiency, autosomal recessive, hereditary thrombophilia due to congenital protein S deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.009276807).
• BP6: Variant 3-93879279-C-T is Benign according to our data. Variant chr3-93879279-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 161343.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00351 (534/152260) while in subpopulation AFR AF = 0.0118 (491/41542). AF 95% confidence interval is 0.011. There are 5 homozygotes in GnomAd4. There are 251 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.1528G>A	p.Val510Met	missense	Exon 13 of 15	NP_000304.2
	PROS1	NM_001314077.2		c.1624G>A	p.Val542Met	missense	Exon 14 of 16	NP_001301006.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROS1	ENST00000394236.9	TSL:1 MANE Select	c.1528G>A	p.Val510Met	missense	Exon 13 of 15	ENSP00000377783.3
	PROS1	ENST00000407433.6	TSL:1	c.1483G>A	p.Val495Met	missense	Exon 13 of 15	ENSP00000385794.2
	PROS1	ENST00000650591.1		c.1624G>A	p.Val542Met	missense	Exon 14 of 16	ENSP00000497376.1

Frequencies

GnomAD3 genomes AF: 0.00350 AC: 533 AN: 152142 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000879 AC: 221 AN: 251446 AF XY: 0.000633

Gnomad AFR exome AF: 0.0112

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000341 AC: 499 AN: 1461768 Hom.: 1 Cov.: 31 AF XY: 0.000296 AC XY: 215 AN XY: 727190

African (AFR) AF: 0.0109 AC: 366 AN: 33474

American (AMR) AF: 0.000559 AC: 25 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000288 AC: 32 AN: 1111912

Other (OTH) AF: 0.000927 AC: 56 AN: 60392

GnomAD4 genome AF: 0.00351 AC: 534 AN: 152260 Hom.: 5 Cov.: 32 AF XY: 0.00337 AC XY: 251 AN XY: 74452

African (AFR) AF: 0.0118 AC: 491 AN: 41542

American (AMR) AF: 0.00150 AC: 23 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68018

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.00400

ESP6500AA AF: 0.0109 AC: 48

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00106 AC: 129

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	2	Thrombophilia due to protein S deficiency, autosomal dominant (4)
-	-	1	PROS1-related disorder (1)
1	-	-	Protein S deficiency disease (1)
-	-	1	Thrombophilia due to protein S deficiency, autosomal dominant;C3281092:Thrombophilia due to protein S deficiency, autosomal recessive (1)
-	-	1	Thrombophilia due to protein S deficiency, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		-0.091
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.035	D
Polyphen		0.58	P
Vest4		0.42
MVP		0.71
MPC		0.25
ClinPred		0.0055	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.75
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs138925964; hg19: chr3-93598123;