16-31094694-C-T

Variant names:

• chr16-31094694-C-T
• rs55894764
• NM_024006.6:c.36G>A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

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 (★).

• Frequency:
  • Genomes: 𝑓 0.013 (32 hom., cov: 32)
  • Exomes 𝑓: 0.012 (198 hom.)
• Consequence: VKORC1 NM_024006.6 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.38

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]

ENSG00000255439 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 318977.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-31094694-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.38 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome 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 gnomad4_exome. There are 8352 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 32 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VKORC1	NM_024006.6	c.36G>A	p.Arg12Arg	synonymous_variant	Exon 1 of 3	ENST00000394975.3	NP_076869.1
VKORC1	NM_001311311.2	c.36G>A	p.Arg12Arg	synonymous_variant	Exon 1 of 4		NP_001298240.1
VKORC1	NM_206824.3	c.36G>A	p.Arg12Arg	synonymous_variant	Exon 1 of 2		NP_996560.1
LOC124903680	XM_047435012.1	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	c.36G>A	p.Arg12Arg	synonymous_variant	Exon 1 of 3	1	NM_024006.6	ENSP00000378426.2
ENSG00000255439	ENST00000529564.1	c.36G>A	p.Arg12Arg	synonymous_variant	Exon 1 of 5	4		ENSP00000431371.1

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1990 AN: 152248 Hom.: 32 Cov.: 32

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

GnomAD3 exomes AF: 0.0151 AC: 3528 AN: 233556 Hom.: 64 AF XY: 0.0144 AC XY: 1855 AN XY: 128710

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 SAS exome AF: 0.00200

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.: 32 AF XY: 0.0115 AC XY: 8352 AN XY: 724318

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.0164

Gnomad4 ASJ exome AF: 0.0224

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00171

Gnomad4 FIN exome AF: 0.0695

Gnomad4 NFE exome AF: 0.0104

Gnomad4 OTH exome AF: 0.0120

GnomAD4 genome AF: 0.0131 AC: 1991 AN: 152366 Hom.: 32 Cov.: 32 AF XY: 0.0154 AC XY: 1150 AN XY: 74510

Gnomad4 AFR AF: 0.00228

Gnomad4 AMR AF: 0.0154

Gnomad4 ASJ AF: 0.0210

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0750

Gnomad4 NFE AF: 0.0111

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00964 Hom.: 6

Bravo AF: 0.00914

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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	15
DANN	Benign	0.94
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7

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

LitVar

Other links and lift over

dbSNP: rs55894764; hg19: chr16-31106015;