rs199469491

chr3-93892993-A-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP4_Strong BP6

The NM_000313.4(PROS1):c.1095T>G(p.Asn365Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000772 in 1,613,426 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (9 hom.)
• Consequence: PROS1 NM_000313.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.74

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 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, 4 uncertain in NM_000313.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.010071516).
• BP6: Variant 3-93892993-A-C is Benign according to our data. Variant chr3-93892993-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 161352.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROS1	NM_000313.4	c.1095T>G	p.Asn365Lys	missense_variant	10/15	ENST00000394236.9
PROS1	NM_001314077.2	c.1191T>G	p.Asn397Lys	missense_variant	11/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROS1	ENST00000394236.9	c.1095T>G	p.Asn365Lys	missense_variant	10/15	1	NM_000313.4	P1

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 220 AN: 152206 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00165 AC: 415 AN: 251384 Hom.: 1 AF XY: 0.00163 AC XY: 221 AN XY: 135880

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000489

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0146

Gnomad NFE exome AF: 0.000616

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.000702 AC: 1025 AN: 1461102 Hom.: 9 Cov.: 31 AF XY: 0.000684 AC XY: 497 AN XY: 726894

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0142

Gnomad4 NFE exome AF: 0.000170

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.00144 AC: 220 AN: 152324 Hom.: 1 Cov.: 32 AF XY: 0.00226 AC XY: 168 AN XY: 74486

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0179

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000430 Hom.: 0

Bravo AF: 0.000140

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00147 AC: 178

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Thrombophilia due to protein S deficiency, autosomal dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

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

Protein S deficiency disease Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

-

- -

Thrombophilia due to protein S deficiency, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 04, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D;.;.;D;.;.
Eigen	Benign	-0.026
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.89	D
MetaRNN	Benign	0.010	T;T;T;T;T;T
MetaSVM	Uncertain	-0.040	T
MutationAssessor	Pathogenic	3.0	M;.;.;M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.4	N;.;.;.;.;.
REVEL	Uncertain	0.48
Sift	Benign	0.29	T;.;.;.;.;.
Sift4G	Benign	0.25	T;.;.;.;.;.
Polyphen		1.0	D;.;.;D;.;.
Vest4		0.90
MutPred		0.56		Gain of methylation at N365 (P = 0.0271);.;.;Gain of methylation at N365 (P = 0.0271);Gain of methylation at N365 (P = 0.0271);.;
MVP		0.79
MPC		0.91
ClinPred		0.15	T
GERP RS		0.65
Varity_R		0.22
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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

Other links and lift over

dbSNP: rs199469491; hg19: chr3-93611837;