chr16-31093850-G-A

Variant names:

• chr16-31093850-G-A
• rs13336384
• NM_024006.6:c.174-429C>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.174-429C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00993 in 285,144 control chromosomes in the GnomAD database, including 91 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 0.017 (85 hom., cov: 29)
  • Exomes 𝑓: 0.0023 (6 hom.)
• Consequence: VKORC1 NM_024006.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.26
• Publications: 6 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0563 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VKORC1	NM_024006.6	c.174-429C>T		intron_variant	Intron 1 of 2	ENST00000394975.3	NP_076869.1
VKORC1	NM_001311311.2	c.174-429C>T		intron_variant	Intron 1 of 3		NP_001298240.1
VKORC1	NM_206824.3	c.173+707C>T		intron_variant	Intron 1 of 1		NP_996560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VKORC1	ENST00000394975.3	c.174-429C>T		intron_variant	Intron 1 of 2	1	NM_024006.6	ENSP00000378426.2
ENSG00000255439	ENST00000529564.1	c.174-429C>T		intron_variant	Intron 1 of 4	4		ENSP00000431371.1

Frequencies

GnomAD3 genomes AF: 0.0168 AC: 2522 AN: 150276 Hom.: 85 Cov.: 29

Gnomad AFR AF: 0.0583

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00604

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000253

Gnomad OTH AF: 0.00977

GnomAD4 exome AF: 0.00226 AC: 305 AN: 134770 Hom.: 6 Cov.: 4 AF XY: 0.00170 AC XY: 121 AN XY: 71338

African (AFR) AF: 0.0565 AC: 247 AN: 4370

American (AMR) AF: 0.00361 AC: 19 AN: 5262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3594

East Asian (EAS) AF: 0.00 AC: 0 AN: 6560

South Asian (SAS) AF: 0.000156 AC: 3 AN: 19246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6042

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 530

European-Non Finnish (NFE) AF: 0.0000856 AC: 7 AN: 81784

Other (OTH) AF: 0.00393 AC: 29 AN: 7382

GnomAD4 genome AF: 0.0168 AC: 2527 AN: 150374 Hom.: 85 Cov.: 29 AF XY: 0.0166 AC XY: 1219 AN XY: 73320

African (AFR) AF: 0.0583 AC: 2398 AN: 41150

American (AMR) AF: 0.00604 AC: 91 AN: 15074

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3438

East Asian (EAS) AF: 0.00 AC: 0 AN: 5104

South Asian (SAS) AF: 0.000211 AC: 1 AN: 4744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10376

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

European-Non Finnish (NFE) AF: 0.000253 AC: 17 AN: 67220

Other (OTH) AF: 0.00967 AC: 20 AN: 2068

Alfa AF: 0.00477 Hom.: 18

Bravo AF: 0.0190

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.5
DANN	Benign	0.61
PhyloP100		-1.3
PromoterAI		0.0028	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: rs13336384; hg19: chr16-31105171;