NM_000313.4:c.835C>T

Variant names:

• chr3-93898462-G-A
• rs121918475
• NM_000313.4:c.835C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000313.4(PROS1):​c.835C>T​(p.Gln279*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PROS1 NM_000313.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.246
• Publications: 4 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-93898462-G-A is Pathogenic according to our data. Variant chr3-93898462-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 13322.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROS1	NM_000313.4	c.835C>T	p.Gln279*	stop_gained	Exon 8 of 15	ENST00000394236.9	NP_000304.2
PROS1	NM_001314077.2	c.931C>T	p.Gln311*	stop_gained	Exon 9 of 16		NP_001301006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROS1	ENST00000394236.9	c.835C>T	p.Gln279*	stop_gained	Exon 8 of 15	1	NM_000313.4	ENSP00000377783.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460436 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726526

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.00 AC: 0 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110978

Other (OTH) AF: 0.00 AC: 0 AN: 60310

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Aug 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln279*) in the PROS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PROS1 are known to be pathogenic (PMID: 9241758). This premature translational stop signal has been observed in individual(s) with protein S deficiency (PMID: 10447256). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 13322). This variant is also known as Q238X. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.021
FATHMM_MKL	Uncertain	0.80	D
PhyloP100		0.25
Vest4		0.77
GERP RS		1.2
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121918475; hg19: chr3-93617306;