rs8178610

Positions:

• chr3-93927552-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000313.4(PROS1):​c.77-145G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.411 in 964,236 control chromosomes in the GnomAD database, including 86,417 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.35 (10729 hom., cov: 30)
  • Exomes 𝑓: 0.42 (75688 hom.)
• Consequence: PROS1 NM_000313.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.146

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 3-93927552-C-T is Benign according to our data. Variant chr3-93927552-C-T is described in ClinVar as [Benign]. Clinvar id is 1264572.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.507 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROS1	NM_000313.4	c.77-145G>A		intron_variant		ENST00000394236.9
PROS1	NM_001314077.2	c.173-145G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROS1	ENST00000394236.9	c.77-145G>A		intron_variant		1	NM_000313.4	P1

Frequencies

GnomAD3 genomes AF: 0.355 AC: 53824 AN: 151642 Hom.: 10723 Cov.: 30

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.490

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.320

Gnomad EAS AF: 0.525

Gnomad SAS AF: 0.502

Gnomad FIN AF: 0.468

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.435

Gnomad OTH AF: 0.366

GnomAD4 exome AF: 0.422 AC: 342726 AN: 812476 Hom.: 75688 AF XY: 0.427 AC XY: 175917 AN XY: 412398

Gnomad4 AFR exome AF: 0.142

Gnomad4 AMR exome AF: 0.319

Gnomad4 ASJ exome AF: 0.313

Gnomad4 EAS exome AF: 0.535

Gnomad4 SAS exome AF: 0.505

Gnomad4 FIN exome AF: 0.480

Gnomad4 NFE exome AF: 0.422

Gnomad4 OTH exome AF: 0.401

GnomAD4 genome AF: 0.355 AC: 53834 AN: 151760 Hom.: 10729 Cov.: 30 AF XY: 0.360 AC XY: 26679 AN XY: 74132

Gnomad4 AFR AF: 0.159

Gnomad4 AMR AF: 0.347

Gnomad4 ASJ AF: 0.320

Gnomad4 EAS AF: 0.524

Gnomad4 SAS AF: 0.502

Gnomad4 FIN AF: 0.468

Gnomad4 NFE AF: 0.435

Gnomad4 OTH AF: 0.367

Alfa AF: 0.420 Hom.: 6500

Bravo AF: 0.334

Asia WGS AF: 0.481 AC: 1669 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.7
DANN	Benign	0.83

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: rs8178610; hg19: chr3-93646396;