chr3-93877089-T-G

Variant names:

• chr3-93877089-T-G
• rs139479630
• NM_000313.4:c.1747A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1 PP2 BP4_Moderate

The NM_000313.4(PROS1):​c.1747A>C​(p.Asn583His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,612,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: PROS1 NM_000313.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.0340
• 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 1 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, thrombophilia due to protein S deficiency, autosomal recessive, hereditary thrombophilia due to congenital protein S deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2574786).

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.1747A>C	p.Asn583His	missense	Exon 14 of 15	NP_000304.2	A0A0S2Z4K3
	PROS1	NM_001314077.2		c.1843A>C	p.Asn615His	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.1747A>C	p.Asn583His	missense	Exon 14 of 15	ENSP00000377783.3	P07225
	PROS1	ENST00000407433.6	TSL:1	c.1702A>C	p.Asn568His	missense	Exon 14 of 15	ENSP00000385794.2	G5E9F8
	PROS1	ENST00000650591.1		c.1843A>C	p.Asn615His	missense	Exon 15 of 16	ENSP00000497376.1	A0A0S2Z4L3

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.000176

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000107 AC: 27 AN: 251454 AF XY: 0.000132

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000189 AC: 276 AN: 1460760 Hom.: 0 Cov.: 30 AF XY: 0.000201 AC XY: 146 AN XY: 726748

African (AFR) AF: 0.0000299 AC: 1 AN: 33446

American (AMR) AF: 0.000134 AC: 6 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000236 AC: 262 AN: 1111046

Other (OTH) AF: 0.0000829 AC: 5 AN: 60340

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74320

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.000393 AC: 6 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

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: 0.000176 AC: 12 AN: 68034

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000176 Hom.: 0

Bravo AF: 0.000155

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Retinal dystrophy (1)
-	1	-	Thrombophilia due to protein S deficiency, autosomal dominant (1)
-	1	-	Thrombophilia due to protein S deficiency, autosomal dominant;C3281092:Thrombophilia due to protein S deficiency, autosomal recessive (1)
-	1	-	Thrombophilia due to protein S deficiency, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	2.3
DANN	Benign	0.80
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.67	N
PhyloP100		0.034
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.12
Sift	Benign	0.14	T
Sift4G	Benign	0.14	T
Polyphen		0.0040	B
Vest4		0.39
MVP		0.50
MPC		0.24
ClinPred		0.029	T
GERP RS		-3.1
Varity_R		0.044
gMVP		0.49
Mutation Taster		=14/86	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs139479630; hg19: chr3-93595933; COSMIC: COSV67775564;