16-31094694-C-T

Position:

chr16-31094694-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BS1BS2

The ENST00000394975.3(VKORC1):c.36G>A(p.Arg12=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,608,310 control chromosomes in the GnomAD database, including 230 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. R12R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.013 ( 32 hom., cov: 32)

Exomes 𝑓: 0.012 ( 198 hom. )

Consequence

VKORC1
ENST00000394975.3 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.38

Variant links:

Genes affected

VKORC1 (HGNC:23663): (vitamin K epoxide reductase complex subunit 1) This gene encodes the catalytic subunit of the vitamin K epoxide reductase complex, which is responsible for the reduction of inactive vitamin K 2,3-epoxide to active vitamin K in the endoplasmic reticulum membrane. Vitamin K is a required co-factor for carboxylation of glutamic acid residues by vitamin K-dependent gamma-carboxylase in blood-clotting enzymes. Allelic variation in this gene is associated with vitamin k-dependent clotting factors combined deficiency of 2, and increased resistance or sensitivity to warfarin, an inhibitor of vitamin K epoxide reductase. Pseudogenes of this gene are located on chromosomes 1 and X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]

VKORC1 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.34).

BP6

Variant 16-31094694-C-T is Benign according to our data. Variant chr16-31094694-C-T is described in ClinVar as [Benign]. Clinvar id is 318977.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-31094694-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=1.38 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0118 (17223/1455944) while in subpopulation AMR AF= 0.0164 (729/44336). AF 95% confidence interval is 0.0155. There are 198 homozygotes in gnomad4_exome. There are 8352 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 32 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VKORC1	NM_024006.6 linkuse as main transcript	c.36G>A	p.Arg12=	synonymous_variant	1/3	ENST00000394975.3	NP_076869.1
VKORC1	NM_001311311.2 linkuse as main transcript	c.36G>A	p.Arg12=	synonymous_variant	1/4		NP_001298240.1
VKORC1	NM_206824.3 linkuse as main transcript	c.36G>A	p.Arg12=	synonymous_variant	1/2		NP_996560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VKORC1	ENST00000394975.3 linkuse as main transcript	c.36G>A	p.Arg12=	synonymous_variant	1/3	1	NM_024006.6	ENSP00000378426	P1	Q9BQB6-1
	ENST00000624508.1 linkuse as main transcript	n.968C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.0131

AC:

1990

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00229

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0155

Gnomad ASJ

AF:

0.0210

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0750

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0111

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.0151

AC:

3528

AN:

233556

Hom.:

AF XY:

0.0144

AC XY:

1855

AN XY:

128710

show subpopulations

Gnomad AFR exome

AF:

0.00210

Gnomad AMR exome

AF:

0.0158

Gnomad ASJ exome

AF:

0.0226

Gnomad EAS exome

AF:

0.0000559

Gnomad SAS exome

AF:

0.00200

Gnomad FIN exome

AF:

0.0735

Gnomad NFE exome

AF:

0.0117

Gnomad OTH exome

AF:

0.0230

GnomAD4 exome

AF:

0.0118

AC:

17223

AN:

1455944

Hom.:

198

Cov.:

AF XY:

0.0115

AC XY:

8352

AN XY:

724318

show subpopulations

Gnomad4 AFR exome

AF:

0.00120

Gnomad4 AMR exome

AF:

0.0164

Gnomad4 ASJ exome

AF:

0.0224

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00171

Gnomad4 FIN exome

AF:

0.0695

Gnomad4 NFE exome

AF:

0.0104

Gnomad4 OTH exome

AF:

0.0120

GnomAD4 genome

AF:

0.0131

AC:

1991

AN:

152366

Hom.:

Cov.:

AF XY:

0.0154

AC XY:

1150

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.00228

Gnomad4 AMR

AF:

0.0154

Gnomad4 ASJ

AF:

0.0210

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.0750

Gnomad4 NFE

AF:

0.0111

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.00964

Hom.:

Bravo

AF:

0.00914

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Vitamin K-dependent clotting factors, combined deficiency of, type 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

-0.34

CADD

Benign

DANN

Benign

0.94

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over