rs8178648

Positions:

• chr3-93886895-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
PROS1	NM_000313.4	c.1156-392A>G		intron_variant		ENST00000394236.9	NP_000304.2
PROS1	NM_001314077.2	c.1252-392A>G		intron_variant			NP_001301006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROS1	ENST00000394236.9	c.1156-392A>G		intron_variant		1	NM_000313.4	ENSP00000377783	P1

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

Gnomad4 AFR AF: 0.150

Gnomad4 AMR AF: 0.0414

Gnomad4 ASJ AF: 0.0425

Gnomad4 EAS AF: 0.0316

Gnomad4 SAS AF: 0.0629

Gnomad4 FIN AF: 0.0589

Gnomad4 NFE AF: 0.0520

Gnomad4 OTH AF: 0.0670

Alfa AF: 0.0634 Hom.: 55

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs8178648; hg19: chr3-93605739;