16-31092854-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000319788.11(VKORC1):c.294G>A(p.Ser98=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000936 in 1,013,254 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00091 (6 hom.)
• Consequence: VKORC1 ENST00000319788.11 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.454

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 16-31092854-C-T is Benign according to our data. Variant chr16-31092854-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3045115.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VKORC1	NM_024006.6	c.283+458G>A		intron_variant		ENST00000394975.3
VKORC1	NM_001311311.2	c.296G>A	p.Arg99His	missense_variant	3/4
VKORC1	NM_206824.3	c.174-1512G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VKORC1	ENST00000394975.3	c.283+458G>A		intron_variant		1	NM_024006.6	P1

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 163 AN: 151596 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000593

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000692

Gnomad OTH AF: 0.000967

GnomAD3 exomes AF: 0.00230 AC: 191 AN: 82994 Hom.: 2 AF XY: 0.00234 AC XY: 109 AN XY: 46632

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000753

Gnomad ASJ exome AF: 0.0301

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000687

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000782

Gnomad OTH exome AF: 0.00330

GnomAD4 exome AF: 0.000911 AC: 785 AN: 861540 Hom.: 6 Cov.: 12 AF XY: 0.000904 AC XY: 386 AN XY: 427030

Gnomad4 AFR exome AF: 0.00156

Gnomad4 AMR exome AF: 0.000642

Gnomad4 ASJ exome AF: 0.0278

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000775

Gnomad4 FIN exome AF: 0.000173

Gnomad4 NFE exome AF: 0.000464

Gnomad4 OTH exome AF: 0.00218

GnomAD4 genome AF: 0.00107 AC: 163 AN: 151714 Hom.: 1 Cov.: 31 AF XY: 0.00111 AC XY: 82 AN XY: 74116

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000593

Gnomad4 ASJ AF: 0.0274

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000692

Gnomad4 OTH AF: 0.000957

Alfa AF: 0.00386 Hom.: 1

Bravo AF: 0.00120

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

VKORC1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2019

This variant is classified as likely 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_noAF	Benign	-0.90
Cadd	Benign	1.1
Dann	Benign	0.63

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

Other links and lift over

dbSNP: rs370105350; hg19: chr16-31104175;