chr3-93908968-G-A

Position:

• chr3-93908968-G-A

Variant summary

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

The NM_000313.4(PROS1):​c.346+1651C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.892 in 152,190 control chromosomes in the GnomAD database, including 60,601 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 0.89 (60601 hom., cov: 31)
• Consequence: PROS1 NM_000313.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0250

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=-1.03).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.905 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROS1	NM_000313.4	c.346+1651C>T		intron_variant		ENST00000394236.9	NP_000304.2
PROS1	NM_001314077.2	c.442+1651C>T		intron_variant			NP_001301006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROS1	ENST00000394236.9	c.346+1651C>T		intron_variant		1	NM_000313.4	ENSP00000377783.3

Frequencies

GnomAD3 genomes AF: 0.892 AC: 135648 AN: 152074 Hom.: 60561 Cov.: 31

Gnomad AFR AF: 0.851

Gnomad AMI AF: 0.808

Gnomad AMR AF: 0.899

Gnomad ASJ AF: 0.861

Gnomad EAS AF: 0.890

Gnomad SAS AF: 0.893

Gnomad FIN AF: 0.938

Gnomad MID AF: 0.835

Gnomad NFE AF: 0.911

Gnomad OTH AF: 0.882

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

GnomAD4 genome AF: 0.892 AC: 135749 AN: 152190 Hom.: 60601 Cov.: 31 AF XY: 0.893 AC XY: 66479 AN XY: 74414

Gnomad4 AFR AF: 0.851

Gnomad4 AMR AF: 0.900

Gnomad4 ASJ AF: 0.861

Gnomad4 EAS AF: 0.890

Gnomad4 SAS AF: 0.892

Gnomad4 FIN AF: 0.938

Gnomad4 NFE AF: 0.911

Gnomad4 OTH AF: 0.881

Alfa AF: 0.897 Hom.: 8818

Bravo AF: 0.885

Asia WGS AF: 0.883 AC: 3073 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.3
DANN	Benign	0.52

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: rs4857037; hg19: chr3-93627812;