Genetic Variant VKORC1:c.*245G>A (chr16-31090889-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_024006.6(VKORC1):c.*245G>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 0.000155 in 588,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

VKORC1
NM_024006.6 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.359

Publications

0 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

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	Effect	Exon Rank	Protein	UniProt
VKORC1	NM_024006.6	MANE Select	c.*245G>A	3_prime_UTR	Exon 3 of 3	NP_076869.1	Q9BQB6-1
VKORC1	NM_001311311.2		c.*245G>A	3_prime_UTR	Exon 4 of 4	NP_001298240.1
VKORC1	NM_206824.3		c.*348G>A	3_prime_UTR	Exon 2 of 2	NP_996560.1	Q9BQB6-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VKORC1	ENST00000394975.3	TSL:1 MANE Select	c.*245G>A	3_prime_UTR	Exon 3 of 3	ENSP00000378426.2	Q9BQB6-1
VKORC1	ENST00000319788.11	TSL:1	c.*348G>A	3_prime_UTR	Exon 4 of 4	ENSP00000326135.7	Q9BQB6-2
VKORC1	ENST00000354895.4	TSL:1	c.*348G>A	3_prime_UTR	Exon 2 of 2	ENSP00000346969.4	Q9BQB6-3

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000158

AC:

AN:

435910

Hom.:

Cov.:

AF XY:

0.000187

AC XY:

AN XY:

229938

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

12098

American (AMR)

AF:

0.000861

AC:

AN:

17414

Ashkenazi Jewish (ASJ)

AF:

0.00316

AC:

AN:

12668

East Asian (EAS)

AF:

0.00

AC:

AN:

27566

South Asian (SAS)

AF:

0.00

AC:

AN:

44904

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24662

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1844

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

270344

Other (OTH)

AF:

0.000410

AC:

AN:

24410

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000145

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41428

American (AMR)

AF:

0.000720

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000356

Hom.:

Bravo

AF:

0.000230

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.80

PhyloP100

0.36

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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