chr3-93873725-T-G

Position:

• chr3-93873725-T-G

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.*520A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.778 in 152,076 control chromosomes in the GnomAD database, including 46,213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.78 (46213 hom., cov: 32)
  • Exomes 𝑓: 0.77 (618 hom.)
  • Failed GnomAD Quality Control
• Consequence: PROS1 NM_000313.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.28

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=-0.9).
• BP6: Variant 3-93873725-T-G is Benign according to our data. Variant chr3-93873725-T-G is described in ClinVar as [Benign]. Clinvar id is 346871.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.805 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROS1	NM_000313.4	c.*520A>C		3_prime_UTR_variant	15/15	ENST00000394236.9
PROS1	NM_001314077.2	c.*520A>C		3_prime_UTR_variant	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROS1	ENST00000394236.9	c.*520A>C		3_prime_UTR_variant	15/15	1	NM_000313.4	P1

Frequencies

GnomAD3 genomes AF: 0.778 AC: 118197 AN: 151958 Hom.: 46173 Cov.: 32

Gnomad AFR AF: 0.708

Gnomad AMI AF: 0.645

Gnomad AMR AF: 0.798

Gnomad ASJ AF: 0.619

Gnomad EAS AF: 0.784

Gnomad SAS AF: 0.781

Gnomad FIN AF: 0.877

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.811

Gnomad OTH AF: 0.748

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.769 AC: 1603 AN: 2084 Hom.: 618 Cov.: 0 AF XY: 0.760 AC XY: 807 AN XY: 1062

Gnomad4 AFR exome AF: 0.357

Gnomad4 AMR exome AF: 0.824

Gnomad4 ASJ exome AF: 0.625

Gnomad4 EAS exome AF: 0.672

Gnomad4 SAS exome AF: 0.696

Gnomad4 FIN exome AF: 0.682

Gnomad4 NFE exome AF: 0.785

Gnomad4 OTH exome AF: 0.653

GnomAD4 genome AF: 0.778 AC: 118299 AN: 152076 Hom.: 46213 Cov.: 32 AF XY: 0.781 AC XY: 58035 AN XY: 74356

Gnomad4 AFR AF: 0.708

Gnomad4 AMR AF: 0.798

Gnomad4 ASJ AF: 0.619

Gnomad4 EAS AF: 0.784

Gnomad4 SAS AF: 0.780

Gnomad4 FIN AF: 0.877

Gnomad4 NFE AF: 0.811

Gnomad4 OTH AF: 0.748

Alfa AF: 0.765 Hom.: 2313

Bravo AF: 0.766

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Thrombophilia due to protein S deficiency, autosomal dominant Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.3
DANN	Benign	0.76

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: rs9681204; hg19: chr3-93592569;