3-93910681-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PP2 PP5

The NM_000313.4(PROS1):​c.284G>A​(p.Gly95Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00057 in 1,613,280 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (1 hom.)
• Consequence: PROS1 NM_000313.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:5
• Conservation: PhyloP100: 1.66
• Publications: 6 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: Uncertain_significance. The variant received 4 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, 7 uncertain in NM_000313.4
• 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, hereditary thrombophilia due to congenital protein S deficiency, thrombophilia due to protein S deficiency, autosomal recessive, protein S deficiency.
• PP5: Variant 3-93910681-C-T is Pathogenic according to our data. Variant chr3-93910681-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 161354.

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.284G>A	p.Gly95Glu	missense	Exon 4 of 15	NP_000304.2	A0A0S2Z4K3
	PROS1	NM_001314077.2		c.380G>A	p.Gly127Glu	missense	Exon 5 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.284G>A	p.Gly95Glu	missense	Exon 4 of 15	ENSP00000377783.3	P07225
	PROS1	ENST00000407433.6	TSL:1	c.284G>A	p.Gly95Glu	missense	Exon 4 of 15	ENSP00000385794.2	G5E9F8
	PROS1	ENST00000650591.1		c.380G>A	p.Gly127Glu	missense	Exon 5 of 16	ENSP00000497376.1	A0A0S2Z4L3

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152020 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000335 AC: 84 AN: 250584 AF XY: 0.000362

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000592

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000589 AC: 861 AN: 1461142 Hom.: 1 Cov.: 30 AF XY: 0.000585 AC XY: 425 AN XY: 726830

African (AFR) AF: 0.000149 AC: 5 AN: 33456

American (AMR) AF: 0.000403 AC: 18 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: 0.000733 AC: 815 AN: 1111552

Other (OTH) AF: 0.000381 AC: 23 AN: 60364

GnomAD4 genome AF: 0.000388 AC: 59 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74370

African (AFR) AF: 0.000145 AC: 6 AN: 41498

American (AMR) AF: 0.000393 AC: 6 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 68008

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000366 Hom.: 0

Bravo AF: 0.000468

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000313 AC: 38

EpiCase AF: 0.000436

EpiControl AF: 0.000475

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
1	1	-	Protein S deficiency disease (2)
1	-	-	Thrombocytopenia;C1458140:Abnormal bleeding (1)
-	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
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.73	D
Eigen	Benign	0.0061
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	1.1	L
PhyloP100		1.7
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.021	D
Polyphen		0.98	D
Vest4		0.42
MVP		0.97
MPC		0.70
ClinPred		0.11	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.91
Mutation Taster		=23/77	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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; COSMIC: COSV62399812;