rs8178648

Variant names:

• chr3-93886895-T-C
• rs8178648
• NM_000313.4:c.1156-392A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000313.4(PROS1):​c.1156-392A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0775 in 151,528 control chromosomes in the GnomAD database, including 620 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.078 (620 hom., cov: 32)
• Consequence: PROS1 NM_000313.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.25
• Publications: 3 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• hereditary thrombophilia due to congenital protein S deficiency

  Inheritance: AR, SD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• thrombophilia due to protein S deficiency, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROS1	NM_000313.4	c.1156-392A>G		intron_variant	Intron 10 of 14	ENST00000394236.9	NP_000304.2
PROS1	NM_001314077.2	c.1252-392A>G		intron_variant	Intron 11 of 15		NP_001301006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROS1	ENST00000394236.9	c.1156-392A>G		intron_variant	Intron 10 of 14	1	NM_000313.4	ENSP00000377783.3

Frequencies

GnomAD3 genomes AF: 0.0775 AC: 11734 AN: 151422 Hom.: 618 Cov.: 32

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0416

Gnomad ASJ AF: 0.0425

Gnomad EAS AF: 0.0319

Gnomad SAS AF: 0.0633

Gnomad FIN AF: 0.0589

Gnomad MID AF: 0.0548

Gnomad NFE AF: 0.0521

Gnomad OTH AF: 0.0667

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0775 AC: 11747 AN: 151528 Hom.: 620 Cov.: 32 AF XY: 0.0756 AC XY: 5598 AN XY: 74046

African (AFR) AF: 0.150 AC: 6201 AN: 41306

American (AMR) AF: 0.0414 AC: 632 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.0425 AC: 147 AN: 3462

East Asian (EAS) AF: 0.0316 AC: 163 AN: 5162

South Asian (SAS) AF: 0.0629 AC: 302 AN: 4800

European-Finnish (FIN) AF: 0.0589 AC: 611 AN: 10368

Middle Eastern (MID) AF: 0.0559 AC: 16 AN: 286

European-Non Finnish (NFE) AF: 0.0520 AC: 3532 AN: 67874

Other (OTH) AF: 0.0670 AC: 141 AN: 2106

Alfa AF: 0.0616 Hom.: 102

Bravo AF: 0.0788

Asia WGS AF: 0.0640 AC: 224 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.5
DANN	Benign	0.56
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs8178648; hg19: chr3-93605739;