rs7200749

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 2P and 14B. PM1BP4_StrongBP6_ModerateBA1

The ENST00000319788.11(VKORC1):c.440C>T(p.Pro147Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,614,136 control chromosomes in the GnomAD database, including 1,541 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.055 ( 759 hom., cov: 32)

Exomes 𝑓: 0.0069 ( 782 hom. )

Consequence

VKORC1
ENST00000319788.11 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.15

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PM1

In a chain Vitamin K epoxide reductase complex subunit 1 (size 162) in uniprot entity VKOR1_HUMAN there are 24 pathogenic changes around while only 4 benign (86%) in ENST00000319788.11

BP4

Computational evidence support a benign effect (MetaRNN=0.0016042292).

BP6

Variant 16-31091268-G-A is Benign according to our data. Variant chr16-31091268-G-A is described in ClinVar as [Benign]. Clinvar id is 318975.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
VKORC1	NM_024006.6 linkuse as main transcript	c.358C>T	p.Leu120=	synonymous_variant	3/3	ENST00000394975.3
VKORC1	NM_206824.3 linkuse as main transcript	c.248C>T	p.Pro83Leu	missense_variant	2/2
VKORC1	NM_001311311.2 linkuse as main transcript	c.442C>T	p.Leu148=	synonymous_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VKORC1	ENST00000394975.3 linkuse as main transcript	c.358C>T	p.Leu120=	synonymous_variant	3/3	1	NM_024006.6	P1	Q9BQB6-1

Frequencies

GnomAD3 genomes

AF:

0.0553

AC:

8410

AN:

152170

Hom.:

751

Cov.:

show subpopulations

Gnomad AFR

AF:

0.188

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0262

Gnomad ASJ

AF:

0.00518

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00157

Gnomad OTH

AF:

0.0382

GnomAD3 exomes

AF:

0.0156

AC:

3912

AN:

251144

Hom.:

320

AF XY:

0.0119

AC XY:

1614

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.195

Gnomad AMR exome

AF:

0.0119

Gnomad ASJ exome

AF:

0.00626

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00170

Gnomad OTH exome

AF:

0.0104

GnomAD4 exome

AF:

0.00685

AC:

10020

AN:

1461848

Hom.:

782

Cov.:

AF XY:

0.00615

AC XY:

4474

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.206

Gnomad4 AMR exome

AF:

0.0131

Gnomad4 ASJ exome

AF:

0.00612

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00101

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00117

Gnomad4 OTH exome

AF:

0.0148

GnomAD4 genome

AF:

0.0554

AC:

8441

AN:

152288

Hom.:

759

Cov.:

AF XY:

0.0540

AC XY:

4023

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.188

Gnomad4 AMR

AF:

0.0261

Gnomad4 ASJ

AF:

0.00518

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00157

Gnomad4 OTH

AF:

0.0378

Alfa

AF:

0.0334

Hom.:

196

Bravo

AF:

0.0628

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.188

AC:

825

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.0190

AC:

2303

Asia WGS

AF:

0.0310

AC:

109

AN:

3478

EpiCase

AF:

0.00174

EpiControl

AF:

0.00249

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_addAF

Benign

-0.017

BayesDel_noAF

Pathogenic

0.35

Cadd

Benign

9.0

Dann

Uncertain

1.0

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.86

D;D;D;D;D

MetaRNN

Benign

0.0016

T;T;T;T;T

MetaSVM

Benign

-0.92

MutationTaster

Benign

0.47

P;P;P;P;P;P

PROVEAN

Benign

1.8

N;N;N;D;D

REVEL

Uncertain

0.60

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

0.0040

.;B;.;.;.

Vest4

0.21

ClinPred

0.039

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

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

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