chr3-93898462-G-A

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: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• thrombophilia due to protein S deficiency, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• protein S deficiency

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• hereditary thrombophilia due to congenital protein S deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROS1	NM_000313.4	MANE Select	c.835C>T	p.Gln279*	stop_gained	Exon 8 of 15	NP_000304.2	A0A0S2Z4K3
	PROS1	NM_001314077.2		c.931C>T	p.Gln311*	stop_gained	Exon 9 of 16	NP_001301006.1	A0A0S2Z4L3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROS1	ENST00000394236.9	TSL:1 MANE Select	c.835C>T	p.Gln279*	stop_gained	Exon 8 of 15	ENSP00000377783.3	P07225
	PROS1	ENST00000407433.6	TSL:1	c.790C>T	p.Gln264*	stop_gained	Exon 8 of 15	ENSP00000385794.2	G5E9F8
	PROS1	ENST00000650591.1		c.931C>T	p.Gln311*	stop_gained	Exon 9 of 16	ENSP00000497376.1	A0A0S2Z4L3

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Thrombophilia due to protein S deficiency, autosomal dominant (1)
1	-	-	Thrombophilia due to protein S deficiency, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

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;