rs61742245

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 4P and 12B. PM1PM5BP4_StrongBP6_StrongBS2

The ENST00000394975.3(VKORC1):c.106G>T(p.Asp36Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,606,390 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D36G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0015 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 23 hom. )

Consequence

VKORC1
ENST00000394975.3 missense

Scores

Clinical Significance

drug response reviewed by expert panel P:1U:1B:6O:1

Conservation

PhyloP100: 0.946

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 -8 ACMG points.

PM1

In a chain Vitamin K epoxide reductase complex subunit 1 (size 162) in uniprot entity VKOR1_HUMAN there are 27 pathogenic changes around while only 3 benign (90%) in ENST00000394975.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

BP4

Computational evidence support a benign effect (MetaRNN=0.035001844).

BP6

Variant 16-31094624-C-A is Benign according to our data. Variant chr16-31094624-C-A is described in ClinVar as [drug_response]. Clinvar id is 2212.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1, Likely_benign=3, drug_response=1}.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VKORC1	NM_024006.6 linkuse as main transcript	c.106G>T	p.Asp36Tyr	missense_variant	1/3	ENST00000394975.3	NP_076869.1
VKORC1	NM_001311311.2 linkuse as main transcript	c.106G>T	p.Asp36Tyr	missense_variant	1/4		NP_001298240.1
VKORC1	NM_206824.3 linkuse as main transcript	c.106G>T	p.Asp36Tyr	missense_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.106G>T	p.Asp36Tyr	missense_variant	1/3	1	NM_024006.6	ENSP00000378426	P1	Q9BQB6-1
	ENST00000624508.1 linkuse as main transcript	n.898C>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.00148

AC:

226

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.0383

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000514

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00240

AC:

547

AN:

227482

Hom.:

AF XY:

0.00235

AC XY:

295

AN XY:

125414

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00166

Gnomad ASJ exome

AF:

0.0386

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000913

Gnomad FIN exome

AF:

0.0000558

Gnomad NFE exome

AF:

0.000694

Gnomad OTH exome

AF:

0.00460

GnomAD4 exome

AF:

0.00134

AC:

1947

AN:

1454012

Hom.:

Cov.:

AF XY:

0.00143

AC XY:

1032

AN XY:

723218

show subpopulations

Gnomad4 AFR exome

AF:

0.00234

Gnomad4 AMR exome

AF:

0.00166

Gnomad4 ASJ exome

AF:

0.0387

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000642

Gnomad4 FIN exome

AF:

0.0000401

Gnomad4 NFE exome

AF:

0.000418

Gnomad4 OTH exome

AF:

0.00358

GnomAD4 genome

AF:

0.00148

AC:

226

AN:

152378

Hom.:

Cov.:

AF XY:

0.00166

AC XY:

124

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.00176

Gnomad4 ASJ

AF:

0.0383

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000514

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00450

Hom.:

Bravo

AF:

0.00176

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00106

AC:

ExAC

AF:

0.00170

AC:

205

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: drug response

Submissions summary: Pathogenic:1Uncertain:1Benign:6Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	VKORC1: PM5, PP3, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 19, 2023	- -

Warfarin response

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2008

- -

Thrombus

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

VKORC1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 29, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

warfarin response - Dosage

Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Nov 18, 2021

PharmGKB Level of Evidence 2A: Variants in Level 2A clinical annotations are found in PharmGKB’s Tier 1 Very Important Pharmacogenes (VIPs). These variants are in known pharmacogenes, implying causation of drug phenotype is more likely. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2A clinical annotations must be supported by at least two independent publications. Drug-variant association: Dosage

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Uncertain

0.035

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.94

.;.;.;.;.;D

Eigen

Benign

0.056

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.56

LIST_S2

Uncertain

0.89

D;D;D;D;D;D

M_CAP

Pathogenic

0.47

MetaRNN

Benign

0.035

T;T;T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.4

.;.;.;M;M;M

MutationTaster

Benign

0.00015

A;A;A;A;A

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-5.9

.;D;D;D;D;D

REVEL

Pathogenic

0.65

Sift

Benign

0.057

.;T;D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;D;D

Polyphen

1.0, 0.99

.;.;.;D;.;D

Vest4

0.55, 0.45, 0.41, 0.42

MVP

0.84

MPC

1.3

ClinPred

0.12

GERP RS

-0.065

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.67

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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