rs146366248

Variant names:

• chr3-93906059-G-T
• rs146366248
• NM_000313.4:c.431C>A

Your query was ambiguous. Multiple possible variants found:

• chr3-93906059-G-T
• chr3-93906059-G-A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_000313.4(PROS1):​c.431C>A​(p.Thr144Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000631 in 1,614,106 control chromosomes in the GnomAD database, including 4 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (4 hom.)
• Consequence: PROS1 NM_000313.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 2.26
• Publications: 4 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: Benign. The variant received -12 ACMG points.

• 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=0.024283767).
• BP6: Variant 3-93906059-G-T is Benign according to our data. Variant chr3-93906059-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 161347.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000447 (68/152260) while in subpopulation SAS AF = 0.00373 (18/4824). AF 95% confidence interval is 0.00241. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.431C>A	p.Thr144Asn	missense	Exon 5 of 15	NP_000304.2	A0A0S2Z4K3
	PROS1	NM_001314077.2		c.527C>A	p.Thr176Asn	missense	Exon 6 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.431C>A	p.Thr144Asn	missense	Exon 5 of 15	ENSP00000377783.3	P07225
	PROS1	ENST00000407433.6	TSL:1	c.431C>A	p.Thr144Asn	missense	Exon 5 of 15	ENSP00000385794.2	G5E9F8
	PROS1	ENST00000650591.1		c.527C>A	p.Thr176Asn	missense	Exon 6 of 16	ENSP00000497376.1	A0A0S2Z4L3

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000768 AC: 193 AN: 251464 AF XY: 0.000979

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000738

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000650 AC: 950 AN: 1461846 Hom.: 4 Cov.: 32 AF XY: 0.000714 AC XY: 519 AN XY: 727218

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000268 AC: 12 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000421 AC: 11 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00298 AC: 257 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.000539 AC: 599 AN: 1111994

Other (OTH) AF: 0.000811 AC: 49 AN: 60390

GnomAD4 genome AF: 0.000447 AC: 68 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74430

African (AFR) AF: 0.000120 AC: 5 AN: 41552

American (AMR) AF: 0.000196 AC: 3 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68024

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000627 Hom.: 0

Bravo AF: 0.000348

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000758 AC: 92

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000655

EpiControl AF: 0.00107

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	not provided (1)
-	-	1	PROS1-related disorder (1)
-	1	-	Retinal dystrophy (1)
-	-	1	Thrombophilia due to protein S deficiency, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	9.2
DANN	Benign	0.75
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.54	N
PhyloP100		2.3
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.18
Sift	Benign	0.32	T
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.38
MVP		0.77
MPC		0.26
ClinPred		0.011	T
GERP RS		0.13
Varity_R		0.12
gMVP		0.67
Mutation Taster		=92/8	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: rs146366248; hg19: chr3-93624903;