rs17708472

Variant names:

• chr16-31094032-G-A
• rs17708472
• NM_024006.6:c.173+525C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_024006.6(VKORC1):​c.173+525C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 961,844 control chromosomes in the GnomAD database, including 21,266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.16 (2529 hom., cov: 30)
  • Exomes 𝑓: 0.20 (18737 hom.)
• Consequence: VKORC1 NM_024006.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.914
• Publications: 58 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-31094032-G-A is Benign according to our data. Variant chr16-31094032-G-A is described in ClinVar as Benign. ClinVar VariationId is 225960.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VKORC1	NM_024006.6	c.173+525C>T		intron_variant	Intron 1 of 2	ENST00000394975.3	NP_076869.1
VKORC1	NM_001311311.2	c.173+525C>T		intron_variant	Intron 1 of 3		NP_001298240.1
VKORC1	NM_206824.3	c.173+525C>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.173+525C>T		intron_variant	Intron 1 of 2	1	NM_024006.6	ENSP00000378426.2
ENSG00000255439	ENST00000529564.1	c.173+525C>T		intron_variant	Intron 1 of 4	4		ENSP00000431371.1

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24884 AN: 151630 Hom.: 2529 Cov.: 30

Gnomad AFR AF: 0.0627

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.165

GnomAD4 exome AF: 0.204 AC: 165028 AN: 810098 Hom.: 18737 Cov.: 11 AF XY: 0.202 AC XY: 82709 AN XY: 408682

African (AFR) AF: 0.0547 AC: 1080 AN: 19748

American (AMR) AF: 0.131 AC: 2689 AN: 20572

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 2265 AN: 15908

East Asian (EAS) AF: 0.00158 AC: 53 AN: 33460

South Asian (SAS) AF: 0.119 AC: 6601 AN: 55540

European-Finnish (FIN) AF: 0.217 AC: 6718 AN: 30946

Middle Eastern (MID) AF: 0.170 AC: 583 AN: 3428

European-Non Finnish (NFE) AF: 0.233 AC: 137876 AN: 592620

Other (OTH) AF: 0.189 AC: 7163 AN: 37876

GnomAD4 genome AF: 0.164 AC: 24885 AN: 151746 Hom.: 2529 Cov.: 30 AF XY: 0.162 AC XY: 12012 AN XY: 74138

African (AFR) AF: 0.0626 AC: 2595 AN: 41428

American (AMR) AF: 0.162 AC: 2458 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 530 AN: 3464

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5158

South Asian (SAS) AF: 0.106 AC: 509 AN: 4784

European-Finnish (FIN) AF: 0.231 AC: 2429 AN: 10536

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.233 AC: 15785 AN: 67870

Other (OTH) AF: 0.163 AC: 342 AN: 2102

Alfa AF: 0.203 Hom.: 14233

Bravo AF: 0.152

Asia WGS AF: 0.0540 AC: 189 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.8
DANN	Benign	0.82
PhyloP100		0.91
PromoterAI		-0.0074	Neutral
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: rs17708472; hg19: chr16-31105353;