rs863224838

Positions:

• chr3-93893120-AA-ACC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000313.4(PROS1):​c.967delinsGG​(p.Phe323GlyfsTer6) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PROS1 NM_000313.4 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.56

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 Pathogenic. Variant got 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 3-93893121-A-CC is Pathogenic according to our data. Variant chr3-93893121-A-CC is described in ClinVar as [Pathogenic]. Clinvar id is 216868.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROS1	NM_000313.4	c.967delinsGG	p.Phe323GlyfsTer6	frameshift_variant, splice_region_variant	10/15	ENST00000394236.9
PROS1	NM_001314077.2	c.1063delinsGG	p.Phe355GlyfsTer6	frameshift_variant, splice_region_variant	11/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROS1	ENST00000394236.9	c.967delinsGG	p.Phe323GlyfsTer6	frameshift_variant, splice_region_variant	10/15	1	NM_000313.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 23, 2018

For these reasons, this variant has been classified as Pathogenic. Truncating variants in PROS1 are known to be pathogenic. This particular truncation has been reported in the literature in patients affected with protein S deficiency and venous thromboembolism (PMID: 16885060, 18435454, 24014240). This variant segregated with protein S deficiency in several families. This change is also known as c.1113T>GG in the literature. This sequence change deletes 1 nucleotide and inserts 2 nucleotides in exon 10 of the PROS1 mRNA (c.967delTinsGG), causing a frameshift at codon 323. This creates a premature translational stop signal (p.Phe323Glyfs*6) and is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs863224838; hg19: chr3-93611965;