16-31093399-C-T

Position:

chr16-31093399-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM5BP4_Strong

The NM_024006.6(VKORC1):c.196G>A(p.Val66Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000151 in 1,614,158 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V66G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00080 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000083 ( 0 hom. )

Consequence

VKORC1
NM_024006.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:1

Conservation

PhyloP100: 2.83

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a chain Vitamin K epoxide reductase complex subunit 1 (size 162) in uniprot entity VKOR1_HUMAN there are 22 pathogenic changes around while only 0 benign (100%) in NM_024006.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

BP4

Computational evidence support a benign effect (MetaRNN=0.017074674).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VKORC1	NM_024006.6 linkuse as main transcript	c.196G>A	p.Val66Met	missense_variant	2/3	ENST00000394975.3	NP_076869.1
VKORC1	NM_001311311.2 linkuse as main transcript	c.196G>A	p.Val66Met	missense_variant	2/4		NP_001298240.1
VKORC1	NM_206824.3 linkuse as main transcript	c.173+1158G>A		intron_variant			NP_996560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VKORC1	ENST00000394975.3 linkuse as main transcript	c.196G>A	p.Val66Met	missense_variant	2/3	1	NM_024006.6	ENSP00000378426	P1	Q9BQB6-1

Frequencies

GnomAD3 genomes

AF:

0.000802

AC:

122

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00280

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000195

AC:

AN:

251118

Hom.:

AF XY:

0.0000958

AC XY:

AN XY:

135768

show subpopulations

Gnomad AFR exome

AF:

0.00265

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000828

AC:

121

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000715

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00290

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000801

AC:

122

AN:

152274

Hom.:

Cov.:

AF XY:

0.000819

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00279

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000148

Hom.:

Bravo

AF:

0.000903

ESP6500AA

AF:

0.00228

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000264

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Warfarin response

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Apr 12, 2018

This variant has been previously reported in the literature in patients with warfarin resistance (PMID: 15630486). Functional studies demonstrate almost complete loss of activity for the p.Val66Met variant relative to wild type (PMID: 23039877). There are 70 reports of the variant as a heterozygous change in the population database, gnomAD, thus the variant is rare. The p.Val66Met residue is highly conserved among vertebrates, and the methionine substitution is predicted to be damaging by in silico models. Based on the combined evidence, the variant is classified as pathogenic. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.53

T;T;T

M_CAP

Pathogenic

0.47

MetaRNN

Benign

0.017

T;T;T

MetaSVM

Pathogenic

1.0

MutationTaster

Benign

0.60

D;D;D;D;D;D

PROVEAN

Benign

0.40

N;N;N

REVEL

Uncertain

0.40

Sift

Benign

0.14

T;D;D

Sift4G

Pathogenic

0.0

D;D;D

Vest4

0.54

MVP

0.92

ClinPred

0.075

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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