16-31094694-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BS1BS2

The NM_024006.6(VKORC1):c.36G>A(p.Arg12Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,608,310 control chromosomes in the GnomAD database, including 230 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. R12R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.013 ( 32 hom., cov: 32)

Exomes 𝑓: 0.012 ( 198 hom. )

Consequence

VKORC1
NM_024006.6 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.38

Publications

11 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 (BayesDel_noAF=-0.34).

BP6

Variant 16-31094694-C-T is Benign according to our data. Variant chr16-31094694-C-T is described in ClinVar as Benign. ClinVar VariationId is 318977.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=1.38 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0118 (17223/1455944) while in subpopulation AMR AF = 0.0164 (729/44336). AF 95% confidence interval is 0.0155. There are 198 homozygotes in GnomAdExome4. There are 8352 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 32 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VKORC1	NM_024006.6 link	c.36G>A	p.Arg12Arg	synonymous_variant	Exon 1 of 3	ENST00000394975.3	NP_076869.1	Q9BQB6-1A0A0S2Z6I4
VKORC1	NM_001311311.2 link	c.36G>A	p.Arg12Arg	synonymous_variant	Exon 1 of 4		NP_001298240.1	Q9BQB6
VKORC1	NM_206824.3 link	c.36G>A	p.Arg12Arg	synonymous_variant	Exon 1 of 2		NP_996560.1	Q9BQB6-3A0A0S2Z5X7
LOC124903680	XM_047435012.1 link	c.*190G>A		downstream_gene_variant			XP_047290968.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VKORC1	ENST00000394975.3 link	c.36G>A	p.Arg12Arg	synonymous_variant	Exon 1 of 3	1	NM_024006.6	ENSP00000378426.2		Q9BQB6-1
ENSG00000255439	ENST00000529564.1 link	c.36G>A	p.Arg12Arg	synonymous_variant	Exon 1 of 5	4		ENSP00000431371.1		E9PLN8

Frequencies

GnomAD3 genomes

AF:

0.0131

AC:

1990

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00229

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0155

Gnomad ASJ

AF:

0.0210

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0750

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0111

Gnomad OTH

AF:

0.0124

GnomAD2 exomes

AF:

0.0151

AC:

3528

AN:

233556

AF XY:

0.0144

show subpopulations

Gnomad AFR exome

AF:

0.00210

Gnomad AMR exome

AF:

0.0158

Gnomad ASJ exome

AF:

0.0226

Gnomad EAS exome

AF:

0.0000559

Gnomad FIN exome

AF:

0.0735

Gnomad NFE exome

AF:

0.0117

Gnomad OTH exome

AF:

0.0230

GnomAD4 exome

AF:

0.0118

AC:

17223

AN:

1455944

Hom.:

198

Cov.:

AF XY:

0.0115

AC XY:

8352

AN XY:

724318

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

33450

American (AMR)

AF:

0.0164

AC:

729

AN:

44336

Ashkenazi Jewish (ASJ)

AF:

0.0224

AC:

583

AN:

26058

East Asian (EAS)

AF:

0.00

AC:

AN:

39604

South Asian (SAS)

AF:

0.00171

AC:

147

AN:

85900

European-Finnish (FIN)

AF:

0.0695

AC:

3457

AN:

49744

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0104

AC:

11538

AN:

1110922

Other (OTH)

AF:

0.0120

AC:

721

AN:

60178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

1259

2518

3776

5035

6294

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

436

872

1308

1744

2180

<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:

0.0131

AC:

1991

AN:

152366

Hom.:

Cov.:

AF XY:

0.0154

AC XY:

1150

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.00228

AC:

AN:

41588

American (AMR)

AF:

0.0154

AC:

236

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0210

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00166

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0750

AC:

797

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0111

AC:

755

AN:

68044

Other (OTH)

AF:

0.0123

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

107

214

322

429

536

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00964

Hom.:

Bravo

AF:

0.00914

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.94

PhyloP100

1.4

PromoterAI

0.032

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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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