rs17878259

Variant names:

• chr16-31095322-A-G
• rs17878259
• XM_047435012.1:c.57T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000420057.2(VKORC1):​c.243+67T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,469,334 control chromosomes in the GnomAD database, including 20 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 0.0069 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (13 hom.)
• Consequence: VKORC1 ENST00000420057.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0960
• Publications: 2 publications found

Genes affected

LOC124903680 (HGNC:):

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: AR, Unknown Classification: MODERATE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• vitamin K-dependent clotting factors, combined deficiency of, type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0069 (1033/149710) while in subpopulation AFR AF = 0.0242 (979/40510). AF 95% confidence interval is 0.0229. There are 7 homozygotes in GnomAd4. There are 492 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000420057.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VKORC1	ENST00000498155.1	TSL:5	c.270+67T>C		intron	N/A	ENSP00000417662.1	F2Z3Q2
	VKORC1	ENST00000420057.2	TSL:2	c.243+67T>C		intron	N/A	ENSP00000437064.1	H0YF24
	ENSG00000280160	ENST00000624508.1	TSL:6	n.1596A>G		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.00690 AC: 1032 AN: 149614 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00339

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00146

GnomAD4 exome AF: 0.000662 AC: 873 AN: 1319624 Hom.: 13 Cov.: 29 AF XY: 0.000541 AC XY: 348 AN XY: 642732

African (AFR) AF: 0.0263 AC: 761 AN: 28926

American (AMR) AF: 0.00115 AC: 29 AN: 25228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20554

East Asian (EAS) AF: 0.00 AC: 0 AN: 35028

South Asian (SAS) AF: 0.0000306 AC: 2 AN: 65296

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5300

European-Non Finnish (NFE) AF: 0.00000575 AC: 6 AN: 1042784

Other (OTH) AF: 0.00137 AC: 75 AN: 54590

GnomAD4 genome AF: 0.00690 AC: 1033 AN: 149710 Hom.: 7 Cov.: 32 AF XY: 0.00674 AC XY: 492 AN XY: 72968

African (AFR) AF: 0.0242 AC: 979 AN: 40510

American (AMR) AF: 0.00339 AC: 51 AN: 15056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5046

South Asian (SAS) AF: 0.00 AC: 0 AN: 4714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67458

Other (OTH) AF: 0.00144 AC: 3 AN: 2080

Alfa AF: 0.00572 Hom.: 1

Bravo AF: 0.00844

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.3
DANN	Benign	0.78
PhyloP100		-0.096
PromoterAI		0.048	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs17878259; hg19: chr16-31106643;