rs8178626

Positions:

• chr3-93909610-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000313.4(PROS1):​c.346+1009T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 151,820 control chromosomes in the GnomAD database, including 18,124 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 0.47 (18124 hom., cov: 31)
• Consequence: PROS1 NM_000313.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.286

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=-0.98).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.609 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROS1	NM_000313.4	c.346+1009T>A		intron_variant		ENST00000394236.9
PROS1	NM_001314077.2	c.442+1009T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROS1	ENST00000394236.9	c.346+1009T>A		intron_variant		1	NM_000313.4	P1

Frequencies

GnomAD3 genomes AF: 0.469 AC: 71181 AN: 151700 Hom.: 18118 Cov.: 31

Gnomad AFR AF: 0.245

Gnomad AMI AF: 0.531

Gnomad AMR AF: 0.527

Gnomad ASJ AF: 0.482

Gnomad EAS AF: 0.624

Gnomad SAS AF: 0.628

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.551

Gnomad OTH AF: 0.485

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

GnomAD4 genome AF: 0.469 AC: 71206 AN: 151820 Hom.: 18124 Cov.: 31 AF XY: 0.476 AC XY: 35282 AN XY: 74196

Gnomad4 AFR AF: 0.245

Gnomad4 AMR AF: 0.528

Gnomad4 ASJ AF: 0.482

Gnomad4 EAS AF: 0.624

Gnomad4 SAS AF: 0.628

Gnomad4 FIN AF: 0.570

Gnomad4 NFE AF: 0.551

Gnomad4 OTH AF: 0.486

Alfa AF: 0.505 Hom.: 2543

Bravo AF: 0.452

Asia WGS AF: 0.585 AC: 2032 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.3
DANN	Benign	0.50

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: rs8178626; hg19: chr3-93628454;