VKORC1 p.Pro147Leu

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 10/17 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, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.15

Publications

25 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

new If you want to explore the variant's impact on the transcript ENST00000319788.11, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

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 VariationId is 318975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000319788.11. 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.358C>T	p.Leu120Leu	synonymous	Exon 3 of 3	NP_076869.1	Q9BQB6-1
VKORC1	NM_206824.3		c.248C>T	p.Pro83Leu	missense	Exon 2 of 2	NP_996560.1	Q9BQB6-3
VKORC1	NM_001311311.2		c.442C>T	p.Leu148Leu	synonymous	Exon 4 of 4	NP_001298240.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VKORC1	ENST00000319788.11	TSL:1	c.440C>T	p.Pro147Leu	missense	Exon 4 of 4	ENSP00000326135.7	Q9BQB6-2
VKORC1	ENST00000354895.4	TSL:1	c.248C>T	p.Pro83Leu	missense	Exon 2 of 2	ENSP00000346969.4	Q9BQB6-3
VKORC1	ENST00000394975.3	TSL:1 MANE Select	c.358C>T	p.Leu120Leu	synonymous	Exon 3 of 3	ENSP00000378426.2	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

GnomAD2 exomes

AF:

0.0156

AC:

3912

AN:

251144

AF XY:

0.0119

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 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

African (AFR)

AF:

0.206

AC:

6882

AN:

33480

American (AMR)

AF:

0.0131

AC:

588

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00612

AC:

160

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.00101

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.0184

AC:

106

AN:

5768

European-Non Finnish (NFE)

AF:

0.00117

AC:

1299

AN:

1112012

Other (OTH)

AF:

0.0148

AC:

894

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

649

1299

1948

2598

3247

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

240

480

720

960

1200

<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:

0.0554

AC:

8441

AN:

152288

Hom.:

759

Cov.:

AF XY:

0.0540

AC XY:

4023

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.188

AC:

7822

AN:

41542

American (AMR)

AF:

0.0261

AC:

400

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00518

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5176

South Asian (SAS)

AF:

0.000622

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00157

AC:

107

AN:

68030

Other (OTH)

AF:

0.0378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

351

702

1054

1405

1756

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

240

320

400

<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:

0.0182

Hom.:

369

Bravo

AF:

0.0628

Asia WGS

AF:

0.0310

AC:

109

AN:

3478

EpiCase

AF:

0.00174

EpiControl

AF:

0.00249

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.017

BayesDel_noAF

Pathogenic

0.35

CADD

Benign

9.0

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0016

MetaSVM

Benign

-0.92

PhyloP100

2.2

PROVEAN

Benign

1.8

REVEL

Uncertain

0.60

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Mutation Taster

=94/6

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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