NM_000313.4:c.284G>T

Variant names:

• chr3-93910681-C-A
• rs144526169
• NM_000313.4:c.284G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_000313.4(PROS1):​c.284G>T​(p.Gly95Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G95E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PROS1 NM_000313.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.66
• Publications: 0 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: Likely_pathogenic. The variant received 9 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, 6 uncertain 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 chr3-93910681-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 161354.
• 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, 0.844

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROS1	NM_000313.4	c.284G>T	p.Gly95Val	missense_variant	Exon 4 of 15	ENST00000394236.9	NP_000304.2
PROS1	NM_001314077.2	c.380G>T	p.Gly127Val	missense_variant	Exon 5 of 16		NP_001301006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROS1	ENST00000394236.9	c.284G>T	p.Gly95Val	missense_variant	Exon 4 of 15	1	NM_000313.4	ENSP00000377783.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461148 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726834

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 86158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111558

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D;.;.;D;.;.
Eigen	Benign	0.050
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.74	.;T;T;T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	1.1	L;.;.;L;.;.
PhyloP100		1.7
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.2	D;.;.;.;.;.
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0090	D;.;.;.;.;.
Sift4G	Uncertain	0.0070	D;.;.;.;.;.
Polyphen		0.99	D;.;.;D;.;.
Vest4		0.69
MutPred		0.65		Gain of catalytic residue at G95 (P = 0.0487);.;.;Gain of catalytic residue at G95 (P = 0.0487);Gain of catalytic residue at G95 (P = 0.0487);Gain of catalytic residue at G95 (P = 0.0487);
MVP		0.98
MPC		0.93
ClinPred		0.93	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.89
Mutation Taster		=31/69	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: rs144526169; hg19: chr3-93629525;