rs199469491

Variant names:

• chr3-93892993-A-C
• rs199469491
• NM_000313.4:c.1095T>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 3P and 9B. PM1 PP2 BP4_Strong BP6 BS2

The NM_000313.4(PROS1):​c.1095T>G​(p.Asn365Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000772 in 1,613,426 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (9 hom.)
• Consequence: PROS1 NM_000313.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.74
• Publications: 9 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 -6 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
• 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=0.010071516).
• BP6: Variant 3-93892993-A-C is Benign according to our data. Variant chr3-93892993-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 161352.
• BS2: High Homozygotes in GnomAdExome4 at 9 AD,AR,SD gene

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.1095T>G	p.Asn365Lys	missense	Exon 10 of 15	NP_000304.2	A0A0S2Z4K3
	PROS1	NM_001314077.2		c.1191T>G	p.Asn397Lys	missense	Exon 11 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.1095T>G	p.Asn365Lys	missense	Exon 10 of 15	ENSP00000377783.3	P07225
	PROS1	ENST00000407433.6	TSL:1	c.1050T>G	p.Asn350Lys	missense	Exon 10 of 15	ENSP00000385794.2	G5E9F8
	PROS1	ENST00000650591.1		c.1191T>G	p.Asn397Lys	missense	Exon 11 of 16	ENSP00000497376.1	A0A0S2Z4L3

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 220 AN: 152206 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00165 AC: 415 AN: 251384 AF XY: 0.00163

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000489

Gnomad FIN exome AF: 0.0146

Gnomad NFE exome AF: 0.000616

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.000702 AC: 1025 AN: 1461102 Hom.: 9 Cov.: 31 AF XY: 0.000684 AC XY: 497 AN XY: 726894

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39684

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86218

European-Finnish (FIN) AF: 0.0142 AC: 760 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5188

European-Non Finnish (NFE) AF: 0.000170 AC: 189 AN: 1111956

Other (OTH) AF: 0.00101 AC: 61 AN: 60326

GnomAD4 genome AF: 0.00144 AC: 220 AN: 152324 Hom.: 1 Cov.: 32 AF XY: 0.00226 AC XY: 168 AN XY: 74486

African (AFR) AF: 0.00 AC: 0 AN: 41584

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.0179 AC: 190 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000430 Hom.: 0

Bravo AF: 0.000140

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00147 AC: 178

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Protein S deficiency disease (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	Pathogenic	0.72
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-0.026
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	-0.040	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		2.7
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.48
Sift	Benign	0.29	T
Sift4G	Benign	0.25	T
Polyphen		1.0	D
Vest4		0.90
MutPred		0.56		Gain of methylation at N365 (P = 0.0271)
MVP		0.79
MPC		0.91
ClinPred		0.15	T
GERP RS		0.65
Varity_R		0.22
gMVP		0.96
Mutation Taster		=6/94	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs199469491; hg19: chr3-93611837;