NM_024006.6:c.*134G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_024006.6(VKORC1):c.*134G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.391 in 1,426,034 control chromosomes in the GnomAD database, including 115,871 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

Frequency

Genomes: 𝑓 0.40 ( 12893 hom., cov: 31)

Exomes 𝑓: 0.39 ( 102978 hom. )

Consequence

VKORC1
NM_024006.6 3_prime_UTR

Scores

Clinical Significance

drug response reviewed by expert panel B:1O:1

Conservation

PhyloP100: 0.00200

Publications

200 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: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.69 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
VKORC1	NM_024006.6 link	c.*134G>A	3_prime_UTR_variant	Exon 3 of 3	ENST00000394975.3	NP_076869.1	Q9BQB6-1A0A0S2Z6I4
VKORC1	NM_001311311.2 link	c.*134G>A	3_prime_UTR_variant	Exon 4 of 4		NP_001298240.1	Q9BQB6
VKORC1	NM_206824.3 link	c.*237G>A	3_prime_UTR_variant	Exon 2 of 2		NP_996560.1	Q9BQB6-3A0A0S2Z5X7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VKORC1	ENST00000394975.3 link	c.*134G>A		3_prime_UTR_variant	Exon 3 of 3	1	NM_024006.6	ENSP00000378426.2		Q9BQB6-1
ENSG00000255439	ENST00000529564.1 link	c.283+2312G>A		intron_variant	Intron 2 of 4	4		ENSP00000431371.1		E9PLN8

Frequencies

GnomAD3 genomes

AF:

0.403

AC:

61172

AN:

151832

Hom.:

12858

Cov.:

show subpopulations

Gnomad AFR

AF:

0.458

Gnomad AMI

AF:

0.321

Gnomad AMR

AF:

0.400

Gnomad ASJ

AF:

0.300

Gnomad EAS

AF:

0.107

Gnomad SAS

AF:

0.712

Gnomad FIN

AF:

0.378

Gnomad MID

AF:

0.250

Gnomad NFE

AF:

0.383

Gnomad OTH

AF:

0.361

GnomAD4 exome

AF:

0.390

AC:

496903

AN:

1274084

Hom.:

102978

Cov.:

AF XY:

0.397

AC XY:

250851

AN XY:

631166

show subpopulations

African (AFR)

AF:

0.464

AC:

13470

AN:

29012

American (AMR)

AF:

0.404

AC:

13444

AN:

33292

Ashkenazi Jewish (ASJ)

AF:

0.322

AC:

7419

AN:

23058

East Asian (EAS)

AF:

0.0949

AC:

3328

AN:

35058

South Asian (SAS)

AF:

0.686

AC:

50916

AN:

74198

European-Finnish (FIN)

AF:

0.388

AC:

16213

AN:

41828

Middle Eastern (MID)

AF:

0.315

AC:

1190

AN:

3782

European-Non Finnish (NFE)

AF:

0.378

AC:

370591

AN:

980348

Other (OTH)

AF:

0.380

AC:

20332

AN:

53508

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

14795

29589

44384

59178

73973

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.403

AC:

61257

AN:

151950

Hom.:

12893

Cov.:

AF XY:

0.407

AC XY:

30239

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.459

AC:

19005

AN:

41426

American (AMR)

AF:

0.400

AC:

6106

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.300

AC:

1041

AN:

3472

East Asian (EAS)

AF:

0.107

AC:

552

AN:

5170

South Asian (SAS)

AF:

0.710

AC:

3425

AN:

4822

European-Finnish (FIN)

AF:

0.378

AC:

3990

AN:

10548

Middle Eastern (MID)

AF:

0.248

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.383

AC:

26002

AN:

67934

Other (OTH)

AF:

0.365

AC:

770

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1820

3640

5459

7279

9099

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.382

Hom.:

43900

Bravo

AF:

0.395

Asia WGS

AF:

0.458

AC:

1591

AN:

3478

ClinVar

Significance: drug response

Submissions summary: Benign:1Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

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

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

warfarin response - Dosage

Other:1

Mar 24, 2021

PharmGKB

Significance:drug response

Review Status:reviewed by expert panel

Collection Method:curation

PharmGKB Level of Evidence 1B: Level 1B clinical annotations describe variant-drug combinations with a high level of evidence supporting the association but no variant-specific prescribing guidance in an annotated clinical guideline or FDA drug label. Level 1B 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

BayesDel_noAF

Benign

-0.89

CADD

Benign

2.1

(source)

DANN

Benign

0.45

PhyloP100

0.0020

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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NM_024006.6:c.*134G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over