rs6123

Positions:

• chr3-93874275-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000313.4(PROS1):​c.2001A>G​(p.Pro667=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 1,613,070 control chromosomes in the GnomAD database, including 136,808 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10408 hom., cov: 32)
  • Exomes 𝑓: 0.41 (126400 hom.)
• Consequence: PROS1 NM_000313.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.268

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 3-93874275-T-C is Benign according to our data. Variant chr3-93874275-T-C is described in ClinVar as [Benign]. Clinvar id is 255811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-93874275-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.268 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROS1	NM_000313.4	c.2001A>G	p.Pro667=	synonymous_variant	15/15	ENST00000394236.9	NP_000304.2
PROS1	NM_001314077.2	c.2097A>G	p.Pro699=	synonymous_variant	16/16		NP_001301006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROS1	ENST00000394236.9	c.2001A>G	p.Pro667=	synonymous_variant	15/15	1	NM_000313.4	ENSP00000377783	P1

Frequencies

GnomAD3 genomes AF: 0.349 AC: 52984 AN: 151904 Hom.: 10400 Cov.: 32

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.440

Gnomad ASJ AF: 0.320

Gnomad EAS AF: 0.555

Gnomad SAS AF: 0.500

Gnomad FIN AF: 0.430

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.406

Gnomad OTH AF: 0.360

GnomAD3 exomes AF: 0.427 AC: 107205 AN: 250796 Hom.: 24110 AF XY: 0.433 AC XY: 58756 AN XY: 135590

Gnomad AFR exome AF: 0.148

Gnomad AMR exome AF: 0.491

Gnomad ASJ exome AF: 0.321

Gnomad EAS exome AF: 0.560

Gnomad SAS exome AF: 0.505

Gnomad FIN exome AF: 0.441

Gnomad NFE exome AF: 0.414

Gnomad OTH exome AF: 0.404

GnomAD4 exome AF: 0.411 AC: 600048 AN: 1461048 Hom.: 126400 Cov.: 51 AF XY: 0.415 AC XY: 301316 AN XY: 726848

Gnomad4 AFR exome AF: 0.139

Gnomad4 AMR exome AF: 0.488

Gnomad4 ASJ exome AF: 0.323

Gnomad4 EAS exome AF: 0.581

Gnomad4 SAS exome AF: 0.506

Gnomad4 FIN exome AF: 0.449

Gnomad4 NFE exome AF: 0.404

Gnomad4 OTH exome AF: 0.395

GnomAD4 genome AF: 0.349 AC: 53000 AN: 152022 Hom.: 10408 Cov.: 32 AF XY: 0.356 AC XY: 26444 AN XY: 74304

Gnomad4 AFR AF: 0.155

Gnomad4 AMR AF: 0.441

Gnomad4 ASJ AF: 0.320

Gnomad4 EAS AF: 0.554

Gnomad4 SAS AF: 0.501

Gnomad4 FIN AF: 0.430

Gnomad4 NFE AF: 0.406

Gnomad4 OTH AF: 0.362

Alfa AF: 0.396 Hom.: 22995

Bravo AF: 0.340

Asia WGS AF: 0.489 AC: 1696 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Thrombophilia due to protein S deficiency, autosomal dominant Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 10494768, 17157360) -

Thrombophilia due to protein S deficiency, autosomal recessive Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	3.7
DANN	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs6123; hg19: chr3-93593119; COSMIC: COSV67775574;