chr16-31091000-C-T

Variant names:

• chr16-31091000-C-T
• rs7294
• NM_024006.6:c.*134G>A

Variant summary

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

The NM_001311311.2(VKORC1):​c.*134G>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 0.391 in 1,426,034 control chromosomes in the GnomAD database, including 115,871 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12893 hom., cov: 31)
  • Exomes 𝑓: 0.39 (102978 hom.)
• Consequence: VKORC1 NM_001311311.2 3_prime_UTR
• Clinical Significance: drug response reviewed by expert panel B:1 O:1
• Conservation: PhyloP100: 0.00200
• Publications: 200 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.69 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001311311.2. 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.*134G>A		3_prime_UTR	Exon 3 of 3	NP_076869.1
	VKORC1	NM_001311311.2		c.*134G>A		3_prime_UTR	Exon 4 of 4	NP_001298240.1
	VKORC1	NM_206824.3		c.*237G>A		3_prime_UTR	Exon 2 of 2	NP_996560.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VKORC1	ENST00000394975.3	TSL:1 MANE Select	c.*134G>A		3_prime_UTR	Exon 3 of 3	ENSP00000378426.2
	VKORC1	ENST00000319788.11	TSL:1	c.*237G>A		3_prime_UTR	Exon 4 of 4	ENSP00000326135.7
	VKORC1	ENST00000354895.4	TSL:1	c.*237G>A		3_prime_UTR	Exon 2 of 2	ENSP00000346969.4

Frequencies

GnomAD3 genomes AF: 0.403 AC: 61172 AN: 151832 Hom.: 12858 Cov.: 31

Gnomad AFR AF: 0.458

Gnomad AMI AF: 0.321

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.712

Gnomad FIN AF: 0.378

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.383

Gnomad OTH AF: 0.361

GnomAD4 exome AF: 0.390 AC: 496903 AN: 1274084 Hom.: 102978 Cov.: 19 AF XY: 0.397 AC XY: 250851 AN XY: 631166

African (AFR) AF: 0.464 AC: 13470 AN: 29012

American (AMR) AF: 0.404 AC: 13444 AN: 33292

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 7419 AN: 23058

East Asian (EAS) AF: 0.0949 AC: 3328 AN: 35058

South Asian (SAS) AF: 0.686 AC: 50916 AN: 74198

European-Finnish (FIN) AF: 0.388 AC: 16213 AN: 41828

Middle Eastern (MID) AF: 0.315 AC: 1190 AN: 3782

European-Non Finnish (NFE) AF: 0.378 AC: 370591 AN: 980348

Other (OTH) AF: 0.380 AC: 20332 AN: 53508

GnomAD4 genome AF: 0.403 AC: 61257 AN: 151950 Hom.: 12893 Cov.: 31 AF XY: 0.407 AC XY: 30239 AN XY: 74270

African (AFR) AF: 0.459 AC: 19005 AN: 41426

American (AMR) AF: 0.400 AC: 6106 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 1041 AN: 3472

East Asian (EAS) AF: 0.107 AC: 552 AN: 5170

South Asian (SAS) AF: 0.710 AC: 3425 AN: 4822

European-Finnish (FIN) AF: 0.378 AC: 3990 AN: 10548

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.383 AC: 26002 AN: 67934

Other (OTH) AF: 0.365 AC: 770 AN: 2110

Alfa AF: 0.382 Hom.: 43900

Bravo AF: 0.395

Asia WGS AF: 0.458 AC: 1591 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Vitamin K-dependent clotting factors, combined deficiency of, type 2 (1)
-	-	-	warfarin response - Dosage (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.1
DANN	Benign	0.45
PhyloP100		0.0020
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs7294; hg19: chr16-31102321;