16-31092864-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_024006.6(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
NM_024006.6 intron

Scores

Splicing: ADA: 0.0002272

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.299

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: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
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: Benign. The variant received -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. GnomAdExome4 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 GnomAdExome4. There are 769 alleles in the male GnomAdExome4 subpopulation. Median coverage is 10. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VKORC1	NM_024006.6 link	c.283+448A>G		intron_variant	Intron 2 of 2	ENST00000394975.3	NP_076869.1	Q9BQB6-1A0A0S2Z6I4
VKORC1	NM_001311311.2 link	c.286A>G	p.Met96Val	missense_variant, splice_region_variant	Exon 3 of 4		NP_001298240.1	Q9BQB6
VKORC1	NM_206824.3 link	c.174-1522A>G		intron_variant	Intron 1 of 1		NP_996560.1	Q9BQB6-3A0A0S2Z5X7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VKORC1	ENST00000394975.3 link	c.283+448A>G		intron_variant	Intron 2 of 2	1	NM_024006.6	ENSP00000378426.2		Q9BQB6-1
ENSG00000255439	ENST00000529564.1 link	c.283+448A>G		intron_variant	Intron 2 of 4	4		ENSP00000431371.1		E9PLN8

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

GnomAD2 exomes

AF:

0.00314

AC:

227

AN:

72394

AF XY:

0.00376

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 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

African (AFR)

AF:

0.00

AC:

AN:

15988

American (AMR)

AF:

0.00

AC:

AN:

14980

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11066

East Asian (EAS)

AF:

0.00

AC:

AN:

10150

South Asian (SAS)

AF:

0.0161

AC:

998

AN:

61806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10978

Middle Eastern (MID)

AF:

0.000285

AC:

AN:

3508

European-Non Finnish (NFE)

AF:

0.0000312

AC:

AN:

640588

Other (OTH)

AF:

0.00145

AC:

AN:

29564

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

125

166

208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000575

AC:

AN:

149544

Hom.:

Cov.:

AF XY:

0.000781

AC XY:

AN XY:

72940

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41220

American (AMR)

AF:

0.0000673

AC:

AN:

14862

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3374

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.0174

AC:

AN:

4780

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10166

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66760

Other (OTH)

AF:

0.000984

AC:

AN:

2032

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Jun 27, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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

PhyloP100

-0.30

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

Mutation Taster

=97/3

polymorphism

(source)

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

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16-31092864-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over