rs104894539

Positions:

chr16-31094645-C-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1_ModeratePM1PM2PP3_StrongPP5

The NM_024006.6(VKORC1):c.85G>T(p.Val29Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000249 in 1,607,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

VKORC1
NM_024006.6 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 3.76

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 Pathogenic. Variant got 11 ACMG points.

PS1

Transcript NM_024006.6 (VKORC1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a transmembrane_region Helical (size 19) in uniprot entity VKOR1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_024006.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

PP5

Variant 16-31094645-C-A is Pathogenic according to our data. Variant chr16-31094645-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2207.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-31094645-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
VKORC1	NM_024006.6 linkuse as main transcript	c.85G>T	p.Val29Leu	missense_variant	1/3	ENST00000394975.3
VKORC1	NM_001311311.2 linkuse as main transcript	c.85G>T	p.Val29Leu	missense_variant	1/4
VKORC1	NM_206824.3 linkuse as main transcript	c.85G>T	p.Val29Leu	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VKORC1	ENST00000394975.3 linkuse as main transcript	c.85G>T	p.Val29Leu	missense_variant	1/3	1	NM_024006.6	P1	Q9BQB6-1
	ENST00000624508.1 linkuse as main transcript	n.919C>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152266

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

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

GnomAD3 exomes

AF:

0.00000433

AC:

AN:

230844

Hom.:

AF XY:

0.00000786

AC XY:

AN XY:

127194

show subpopulations

Gnomad AFR exome

AF:

0.0000723

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1454770

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723766

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000688

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000829

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Warfarin response

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 05, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

.;.;.;.;.;D

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.79

T;T;T;T;T;T

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.6

.;.;.;M;M;M

MutationTaster

Benign

1.0

A;A;A;A;A

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.5

.;D;D;D;D;D

REVEL

Pathogenic

0.86

Sift

Uncertain

0.019

.;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;T;D;T;D;T

Polyphen

1.0, 1.0

.;.;.;D;.;D

Vest4

0.67, 0.88, 0.82, 0.58

MutPred

0.95

Loss of catalytic residue at V29 (P = 0.1021);Loss of catalytic residue at V29 (P = 0.1021);Loss of catalytic residue at V29 (P = 0.1021);Loss of catalytic residue at V29 (P = 0.1021);Loss of catalytic residue at V29 (P = 0.1021);Loss of catalytic residue at V29 (P = 0.1021);

MVP

0.83

MPC

0.97

ClinPred

0.97

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.86

gMVP

0.88

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

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