NM_024006.6:c.174-136C>T

Variant names:

• chr16-31093557-G-A
• rs9934438
• NM_024006.6:c.174-136C>T

Variant summary

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

The NM_024006.6(VKORC1):​c.174-136C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,543,178 control chromosomes in the GnomAD database, including 119,212 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

• Frequency:
  • Genomes: 𝑓 0.32 (9986 hom., cov: 29)
  • Exomes 𝑓: 0.38 (109226 hom.)
• Consequence: VKORC1 NM_024006.6 intron
• Clinical Significance: drug response reviewed by expert panel P:1 B:3 O:4
• Conservation: PhyloP100: 1.31
• Publications: 376 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=-0.72).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.871 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.174-136C>T		intron	N/A	NP_076869.1
	VKORC1	NM_001311311.2		c.174-136C>T		intron	N/A	NP_001298240.1
	VKORC1	NM_206824.3		c.173+1000C>T		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.174-136C>T		intron	N/A	ENSP00000378426.2
	ENSG00000255439	ENST00000529564.1	TSL:4	c.174-136C>T		intron	N/A	ENSP00000431371.1
	VKORC1	ENST00000319788.11	TSL:1	c.174-136C>T		intron	N/A	ENSP00000326135.7

Frequencies

GnomAD3 genomes AF: 0.319 AC: 48370 AN: 151546 Hom.: 9985 Cov.: 29

Gnomad AFR AF: 0.0999

Gnomad AMI AF: 0.442

Gnomad AMR AF: 0.391

Gnomad ASJ AF: 0.500

Gnomad EAS AF: 0.893

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.378

Gnomad OTH AF: 0.390

GnomAD4 exome AF: 0.380 AC: 528705 AN: 1391514 Hom.: 109226 Cov.: 33 AF XY: 0.376 AC XY: 257779 AN XY: 685662

African (AFR) AF: 0.0931 AC: 2942 AN: 31592

American (AMR) AF: 0.451 AC: 16003 AN: 35520

Ashkenazi Jewish (ASJ) AF: 0.491 AC: 12028 AN: 24496

East Asian (EAS) AF: 0.903 AC: 32312 AN: 35766

South Asian (SAS) AF: 0.187 AC: 14562 AN: 77986

European-Finnish (FIN) AF: 0.391 AC: 18952 AN: 48446

Middle Eastern (MID) AF: 0.492 AC: 2528 AN: 5140

European-Non Finnish (NFE) AF: 0.378 AC: 406811 AN: 1074930

Other (OTH) AF: 0.392 AC: 22567 AN: 57638

GnomAD4 genome AF: 0.319 AC: 48369 AN: 151664 Hom.: 9986 Cov.: 29 AF XY: 0.321 AC XY: 23820 AN XY: 74112

African (AFR) AF: 0.0996 AC: 4120 AN: 41372

American (AMR) AF: 0.391 AC: 5952 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1734 AN: 3470

East Asian (EAS) AF: 0.893 AC: 4583 AN: 5132

South Asian (SAS) AF: 0.178 AC: 858 AN: 4812

European-Finnish (FIN) AF: 0.390 AC: 4101 AN: 10506

Middle Eastern (MID) AF: 0.527 AC: 154 AN: 292

European-Non Finnish (NFE) AF: 0.378 AC: 25647 AN: 67848

Other (OTH) AF: 0.389 AC: 818 AN: 2104

Alfa AF: 0.362 Hom.: 25630

Bravo AF: 0.323

Asia WGS AF: 0.460 AC: 1602 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Vitamin K-Dependent Clotting Factors (1)
1	-	-	Warfarin response (2)
-	-	-	acenocoumarol response - Dosage (1)
-	-	-	phenprocoumon response - Dosage (1)
-	-	-	warfarin response - Dosage (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	13
DANN	Benign	0.90
PhyloP100		1.3
PromoterAI		-0.065	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs9934438; hg19: chr16-31104878;