rs17882023

Variant names:

• chr16-31092015-T-C
• rs17882023
• NM_024006.6:c.284-673A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024006.6(VKORC1):​c.284-673A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0786 in 151,654 control chromosomes in the GnomAD database, including 746 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.079 (746 hom., cov: 31)
• Consequence: VKORC1 NM_024006.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.707
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024006.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VKORC1	NM_024006.6	MANE Select	c.284-673A>G		intron	N/A	NP_076869.1
	VKORC1	NM_001311311.2		c.368-673A>G		intron	N/A	NP_001298240.1
	VKORC1	NM_206824.3		c.174-673A>G		intron	N/A	NP_996560.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VKORC1	ENST00000394975.3	TSL:1 MANE Select	c.284-673A>G		intron	N/A	ENSP00000378426.2
	ENSG00000255439	ENST00000529564.1	TSL:4	c.283+1297A>G		intron	N/A	ENSP00000431371.1
	VKORC1	ENST00000319788.11	TSL:1	c.366-673A>G		intron	N/A	ENSP00000326135.7

Frequencies

GnomAD3 genomes AF: 0.0786 AC: 11917 AN: 151540 Hom.: 742 Cov.: 31

Gnomad AFR AF: 0.0173

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.0503

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.0679

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.0949

Gnomad OTH AF: 0.0792

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0786 AC: 11927 AN: 151654 Hom.: 746 Cov.: 31 AF XY: 0.0819 AC XY: 6069 AN XY: 74090

African (AFR) AF: 0.0173 AC: 716 AN: 41398

American (AMR) AF: 0.176 AC: 2668 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.0503 AC: 174 AN: 3462

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5148

South Asian (SAS) AF: 0.0678 AC: 326 AN: 4810

European-Finnish (FIN) AF: 0.135 AC: 1410 AN: 10466

Middle Eastern (MID) AF: 0.0172 AC: 5 AN: 290

European-Non Finnish (NFE) AF: 0.0950 AC: 6445 AN: 67872

Other (OTH) AF: 0.0779 AC: 164 AN: 2104

Alfa AF: 0.0976 Hom.: 120

Bravo AF: 0.0768

Asia WGS AF: 0.0360 AC: 123 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.1
DANN	Benign	0.71
PhyloP100		-0.71
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17882023; hg19: chr16-31103336;