rs142846443

Variant names:

• chr3-93877074-T-C
• rs142846443
• NM_000313.4:c.1762A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM1 PP2 BP4_Strong BP6 BS2_Supporting

The NM_000313.4(PROS1):​c.1762A>G​(p.Thr588Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000436 in 1,613,310 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (3 hom.)
• Consequence: PROS1 NM_000313.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 3.93
• 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: Likely_benign. The variant received -3 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
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.011641026).
• BP6: Variant 3-93877074-T-C is Benign according to our data. Variant chr3-93877074-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 161344.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR,SD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.1762A>G	p.Thr588Ala	missense	Exon 14 of 15	NP_000304.2	A0A0S2Z4K3
	PROS1	NM_001314077.2		c.1858A>G	p.Thr620Ala	missense	Exon 15 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.1762A>G	p.Thr588Ala	missense	Exon 14 of 15	ENSP00000377783.3	P07225
	PROS1	ENST00000407433.6	TSL:1	c.1717A>G	p.Thr573Ala	missense	Exon 14 of 15	ENSP00000385794.2	G5E9F8
	PROS1	ENST00000650591.1		c.1858A>G	p.Thr620Ala	missense	Exon 15 of 16	ENSP00000497376.1	A0A0S2Z4L3

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 64 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000803 AC: 202 AN: 251460 AF XY: 0.000714

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0153

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.000437 AC: 639 AN: 1461130 Hom.: 3 Cov.: 30 AF XY: 0.000440 AC XY: 320 AN XY: 726924

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0155 AC: 404 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.000121 AC: 135 AN: 1111352

Other (OTH) AF: 0.00152 AC: 92 AN: 60362

GnomAD4 genome AF: 0.000421 AC: 64 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.000350 AC XY: 26 AN XY: 74338

African (AFR) AF: 0.0000483 AC: 2 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68034

Other (OTH) AF: 0.000957 AC: 2 AN: 2090

Alfa AF: 0.000764 Hom.: 1

Bravo AF: 0.000480

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000634 AC: 77

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Thrombophilia due to protein S deficiency, autosomal dominant (2)
-	-	1	PROS1-related disorder (1)
-	-	1	Thrombophilia due to protein S deficiency, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	8.7
DANN	Benign	0.81
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.9
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.27	N
REVEL	Uncertain	0.50
Sift	Benign	0.48	T
Sift4G	Benign	0.49	T
Polyphen		0.64	P
Vest4		0.072
MVP		0.82
MPC		0.23
ClinPred		0.056	T
GERP RS		4.6
Varity_R		0.048
gMVP		0.53
Mutation Taster		=81/19	polymorphism

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: rs142846443; hg19: chr3-93595918;