rs886051932

Variant names:

• chr16-31090889-C-T
• rs886051932
• NM_024006.6:c.*245G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_024006.6(VKORC1):​c.*245G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000155 in 588,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: VKORC1 NM_024006.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.359
• Publications: 0 publications found

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

ENSG00000255439 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VKORC1	NM_024006.6	c.*245G>A		3_prime_UTR_variant	Exon 3 of 3	ENST00000394975.3	NP_076869.1
VKORC1	NM_001311311.2	c.*245G>A		3_prime_UTR_variant	Exon 4 of 4		NP_001298240.1
VKORC1	NM_206824.3	c.*348G>A		3_prime_UTR_variant	Exon 2 of 2		NP_996560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VKORC1	ENST00000394975.3	c.*245G>A		3_prime_UTR_variant	Exon 3 of 3	1	NM_024006.6	ENSP00000378426.2
ENSG00000255439	ENST00000529564.1	c.283+2423G>A		intron_variant	Intron 2 of 4	4		ENSP00000431371.1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152158 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000158 AC: 69 AN: 435910 Hom.: 0 Cov.: 5 AF XY: 0.000187 AC XY: 43 AN XY: 229938

African (AFR) AF: 0.00 AC: 0 AN: 12098

American (AMR) AF: 0.000861 AC: 15 AN: 17414

Ashkenazi Jewish (ASJ) AF: 0.00316 AC: 40 AN: 12668

East Asian (EAS) AF: 0.00 AC: 0 AN: 27566

South Asian (SAS) AF: 0.00 AC: 0 AN: 44904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24662

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1844

European-Non Finnish (NFE) AF: 0.0000148 AC: 4 AN: 270344

Other (OTH) AF: 0.000410 AC: 10 AN: 24410

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152158 Hom.: 0 Cov.: 31 AF XY: 0.000242 AC XY: 18 AN XY: 74334

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.000720 AC: 11 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000356 Hom.: 0

Bravo AF: 0.000230

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Vitamin K-dependent clotting factors, combined deficiency of, type 2 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	11
DANN	Benign	0.80
PhyloP100		0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886051932; hg19: chr16-31102210;