16-31094624-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_024006.6(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 (★★★).

Frequency

Genomes: 𝑓 0.0015 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 23 hom. )

Consequence

VKORC1
NM_024006.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.946

Publications

88 publications found

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 Gene-Disease associations (from GenCC):

vitamin K-dependent clotting factors, combined deficiency of, type 2
Inheritance: AR, Unknown Classification: MODERATE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
vitamin K-dependent clotting factors, combined deficiency of, type 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

VKORC1 links:

ENSG00000255439 (HGNC:):

ENSG00000255439 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

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

BS2

High Homozygotes in GnomAd4 at 4 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024006.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VKORC1	NM_024006.6	MANE Select	c.106G>T	p.Asp36Tyr	missense	Exon 1 of 3	NP_076869.1	Q9BQB6-1
VKORC1	NM_001311311.2		c.106G>T	p.Asp36Tyr	missense	Exon 1 of 4	NP_001298240.1
VKORC1	NM_206824.3		c.106G>T	p.Asp36Tyr	missense	Exon 1 of 2	NP_996560.1	Q9BQB6-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VKORC1	ENST00000394975.3	TSL:1 MANE Select	c.106G>T	p.Asp36Tyr	missense	Exon 1 of 3	ENSP00000378426.2	Q9BQB6-1
ENSG00000255439	ENST00000529564.1	TSL:4	c.106G>T	p.Asp36Tyr	missense	Exon 1 of 5	ENSP00000431371.1	E9PLN8
VKORC1	ENST00000319788.11	TSL:1	c.106G>T	p.Asp36Tyr	missense	Exon 1 of 4	ENSP00000326135.7	Q9BQB6-2

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

GnomAD2 exomes

AF:

0.00240

AC:

547

AN:

227482

AF XY:

0.00235

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 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

African (AFR)

AF:

0.00234

AC:

AN:

33398

American (AMR)

AF:

0.00166

AC:

AN:

43900

Ashkenazi Jewish (ASJ)

AF:

0.0387

AC:

1004

AN:

25966

East Asian (EAS)

AF:

0.00

AC:

AN:

39472

South Asian (SAS)

AF:

0.000642

AC:

AN:

85620

European-Finnish (FIN)

AF:

0.0000401

AC:

AN:

49912

Middle Eastern (MID)

AF:

0.00973

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000418

AC:

464

AN:

1109930

Other (OTH)

AF:

0.00358

AC:

215

AN:

60060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

151

301

452

602

753

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00148

AC:

226

AN:

152378

Hom.:

Cov.:

AF XY:

0.00166

AC XY:

124

AN XY:

74516

show subpopulations

African (AFR)

AF:

0.000481

AC:

AN:

41596

American (AMR)

AF:

0.00176

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0383

AC:

133

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000621

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000514

AC:

AN:

68036

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000905

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

ClinVar submissions

Significance:drug response

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Thrombus (1)

Vitamin K-dependent clotting factors, combined deficiency of, type 2 (1)

VKORC1-related disorder (1)

Warfarin response (1)

warfarin response - Dosage (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Uncertain

0.035

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.94

Eigen

Benign

0.056

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.56

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.47

MetaRNN

Benign

0.035

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.4

PhyloP100

0.95

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-5.9

REVEL

Pathogenic

0.65

Sift

Benign

0.057

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.55

MVP

0.84

MPC

1.3

ClinPred

0.12

GERP RS

-0.065

PromoterAI

-0.025

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.67

gMVP

0.93

Mutation Taster

=84/16

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over