chr3-93877155-G-C

Variant names:

• chr3-93877155-G-C
• rs121918476
• NM_000313.4:c.1681C>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_000313.4(PROS1):​c.1681C>G​(p.Arg561Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R561Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PROS1 NM_000313.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 1.04
• 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: Pathogenic. The variant received 11 ACMG points.

• PM1: In a domain Laminin G-like 2 (size 182) in uniprot entity PROS_HUMAN there are 15 pathogenic changes around while only 2 benign (88%) in NM_000313.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-93877155-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 219837.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944

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.1681C>G	p.Arg561Gly	missense	Exon 14 of 15	NP_000304.2
	PROS1	NM_001314077.2		c.1777C>G	p.Arg593Gly	missense	Exon 15 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.1681C>G	p.Arg561Gly	missense	Exon 14 of 15	ENSP00000377783.3
	PROS1	ENST00000407433.6	TSL:1	c.1636C>G	p.Arg546Gly	missense	Exon 14 of 15	ENSP00000385794.2
	PROS1	ENST00000650591.1		c.1777C>G	p.Arg593Gly	missense	Exon 15 of 16	ENSP00000497376.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

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

Protein S deficiency disease Uncertain:1

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D
Eigen	Benign	-0.057
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.054	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.0
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.51
Sift	Benign	0.16	T
Sift4G	Benign	0.11	T
Polyphen		0.85	P
Vest4		0.63
MutPred		0.89		Loss of sheet (P = 0.0037)
MVP		0.87
MPC		0.68
ClinPred		0.66	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.82
Mutation Taster		=29/71	disease causing

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: rs121918476; hg19: chr3-93595999;