NM_024006.6:c.173+486C>A

Variant names:

• chr16-31094071-G-T
• rs13337470
• NM_024006.6:c.173+486C>A

Variant summary

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

The NM_024006.6(VKORC1):​c.173+486C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,263,550 control chromosomes in the GnomAD database, including 14 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 0.0052 (8 hom., cov: 31)
  • Exomes 𝑓: 0.00055 (6 hom.)
• Consequence: VKORC1 NM_024006.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.129
• Publications: 4 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).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00521 (792/152156) while in subpopulation AFR AF = 0.0185 (769/41518). AF 95% confidence interval is 0.0174. There are 8 homozygotes in GnomAd4. There are 383 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR,Unknown gene

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.173+486C>A		intron	N/A	NP_076869.1
	VKORC1	NM_001311311.2		c.173+486C>A		intron	N/A	NP_001298240.1
	VKORC1	NM_206824.3		c.173+486C>A		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.173+486C>A		intron	N/A	ENSP00000378426.2
	ENSG00000255439	ENST00000529564.1	TSL:4	c.173+486C>A		intron	N/A	ENSP00000431371.1
	VKORC1	ENST00000319788.11	TSL:1	c.173+486C>A		intron	N/A	ENSP00000326135.7

Frequencies

GnomAD3 genomes AF: 0.00520 AC: 790 AN: 152038 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00112

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: 0.0000588

Gnomad OTH AF: 0.000956

GnomAD4 exome AF: 0.000551 AC: 612 AN: 1111394 Hom.: 6 Cov.: 15 AF XY: 0.000476 AC XY: 263 AN XY: 552014

African (AFR) AF: 0.0210 AC: 542 AN: 25840

American (AMR) AF: 0.000536 AC: 15 AN: 27990

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18330

East Asian (EAS) AF: 0.00 AC: 0 AN: 37470

South Asian (SAS) AF: 0.0000154 AC: 1 AN: 65076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34100

Middle Eastern (MID) AF: 0.000211 AC: 1 AN: 4742

European-Non Finnish (NFE) AF: 0.0000118 AC: 10 AN: 849808

Other (OTH) AF: 0.000895 AC: 43 AN: 48038

GnomAD4 genome AF: 0.00521 AC: 792 AN: 152156 Hom.: 8 Cov.: 31 AF XY: 0.00515 AC XY: 383 AN XY: 74380

African (AFR) AF: 0.0185 AC: 769 AN: 41518

American (AMR) AF: 0.00111 AC: 17 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68008

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00182 Hom.: 2

Bravo AF: 0.00591

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.0
DANN	Benign	0.50
PhyloP100		0.13
PromoterAI		-0.015	Neutral
Mutation Taster		=100/0	polymorphism

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: rs13337470; hg19: chr16-31105392;