16-31092864-T-C

Position:

chr16-31092864-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000394975.3(VKORC1):c.283+448A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 948,172 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.00058 ( 3 hom., cov: 31)

Exomes 𝑓: 0.0013 ( 17 hom. )

Consequence

VKORC1
ENST00000394975.3 intron

Scores

Splicing: ADA: 0.0002272

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.299

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044502616).

BP6

Variant 16-31092864-T-C is Benign according to our data. Variant chr16-31092864-T-C is described in ClinVar as [Benign]. Clinvar id is 3033207.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00133 (1062/798628) while in subpopulation SAS AF= 0.0161 (998/61806). AF 95% confidence interval is 0.0153. There are 17 homozygotes in gnomad4_exome. There are 769 alleles in male gnomad4_exome subpopulation. Median coverage is 10. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VKORC1	NM_024006.6 linkuse as main transcript	c.283+448A>G		intron_variant		ENST00000394975.3	NP_076869.1
VKORC1	NM_001311311.2 linkuse as main transcript	c.286A>G	p.Met96Val	missense_variant, splice_region_variant	3/4		NP_001298240.1
VKORC1	NM_206824.3 linkuse as main transcript	c.174-1522A>G		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.283+448A>G		intron_variant		1	NM_024006.6	ENSP00000378426	P1	Q9BQB6-1

Frequencies

GnomAD3 genomes

AF:

0.000576

AC:

AN:

149426

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000674

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0173

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000995

GnomAD3 exomes

AF:

0.00314

AC:

227

AN:

72394

Hom.:

AF XY:

0.00376

AC XY:

152

AN XY:

40384

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0176

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000720

Gnomad OTH exome

AF:

0.00238

GnomAD4 exome

AF:

0.00133

AC:

1062

AN:

798628

Hom.:

Cov.:

AF XY:

0.00194

AC XY:

769

AN XY:

396306

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0161

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000312

Gnomad4 OTH exome

AF:

0.00145

GnomAD4 genome

AF:

0.000575

AC:

AN:

149544

Hom.:

Cov.:

AF XY:

0.000781

AC XY:

AN XY:

72940

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000673

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0174

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000984

Alfa

AF:

0.000260

Hom.:

Bravo

AF:

0.000204

ExAC

AF:

0.00764

AC:

108

Asia WGS

AF:

0.00722

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

VKORC1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 27, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.25

CADD

Benign

4.1

DANN

Benign

0.73

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.0021

LIST_S2

Benign

0.32

M_CAP

Benign

0.0077

MetaRNN

Benign

0.0045

MetaSVM

Uncertain

0.26

MutationTaster

Benign

1.0

N;N;N;N;N;N

PROVEAN

Benign

2.9

REVEL

Benign

0.23

Sift

Benign

0.41

Sift4G

Benign

0.73

Polyphen

0.99

Vest4

0.20

MutPred

0.47

Loss of stability (P = 0.0332);

MVP

0.75

ClinPred

0.023

GERP RS

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00023

dbscSNV1_RF

Benign

0.044

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