rs7294

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr16-31091000-C-T
• chr16-31091000-C-A
• chr16-31091000-C-G

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_024006.6(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 cumulative frequency of 0.391 (AC=558,160) in the gnomAD database across 1,426,034 control chromosomes, including 115,871 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.69. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12893 hom., cov: 31)
  • Exomes 𝑓: 0.39 (102978 hom.)
• Consequence: VKORC1 NM_024006.6 3_prime_UTR
• Clinical Significance: drug response reviewed by expert panel B:2 O:1
• Conservation: PhyloP100: 0.00200
• Publications: 46 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):

• coumarin resistance

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• vitamin K-dependent clotting factors, combined deficiency of, type 2

  Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• vitamin K-dependent clotting factors, combined deficiency of, type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000255439 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.6904 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_024006.6. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	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	Prot: NP_076869.1 UniProt:
	VKORC1 NM_001311311.2		c.*134G>A	3_prime_UTR	Exon 4 of 4	Prot: NP_001298240.1
	VKORC1 NM_206824.3		c.*237G>A	3_prime_UTR	Exon 2 of 2	Prot: NP_996560.1 UniProt:

VKORC1 NM_024006.6

MANE Select

HGVSc / HGVSpc.*134G>A

Exon rankExon 3 of 3

3_prime_UTR

Prot: NP_076869.1UniProt: A0A0S2Z6I4Q9BQB6-1

VKORC1 NM_001311311.2

HGVSc / HGVSpc.*134G>A

Exon rankExon 4 of 4

3_prime_UTR

Prot: NP_001298240.1

VKORC1 NM_206824.3

HGVSc / HGVSpc.*237G>A

Exon rankExon 2 of 2

3_prime_UTR

Prot: NP_996560.1UniProt: Q9BQB6-3A0A0S2Z5X7

Ensembl Transcripts

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

VKORC1 ENST00000394975.3

TSL:1MANE Select

HGVSc / HGVSpc.*134G>A

Exon rankExon 3 of 3

3_prime_UTR

Prot: ENSP00000378426.2UniProt: Q9BQB6-1

VKORC1 ENST00000319788.11

TSL:1

HGVSc / HGVSpc.*237G>A

Exon rankExon 4 of 4

3_prime_UTR

Prot: ENSP00000326135.7UniProt: Q9BQB6-2

VKORC1 ENST00000354895.4

TSL:1

HGVSc / HGVSpc.*237G>A

Exon rankExon 2 of 2

3_prime_UTR

Prot: ENSP00000346969.4UniProt: Q9BQB6-3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.403	AC:61172	Hom:12858	AN:151832	Cov:31
GnomAD4 exome	AF: 0.390	AC:496903	Hom:102978	AN:1274084	Cov:19
GnomAD4 genome	AF: 0.403	AC:61257	Hom:12893	AN:151950	Cov:31
TOPMed (Bravo)	AF: 0.395	AC:104469	Hom:21423	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.382	AC:232770	Hom:45947	AN:609240	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.358	AC:838	Hom:158	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0897	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.377	AC:113	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.458	AC:1591	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.0740	AC:533	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.347	AC:61	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0913	AC:11167	Hom:506	AN:122326	Cov:
Turkish Variome	AF: 0.320	AC:495	Hom:81	AN:1546	Cov:
UK10K	AF: 0.380	AC:2873	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.0906	AC:812	Hom:43	AN:8960	Cov:

Showing 15 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.284	19620	69008	0.280	33247	118536

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Vitamin K-dependent clotting factors, combined deficiency of, type 2 (1)
-	-	-	warfarin response - Dosage (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	5.2
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.1
DANN	Benign	0.45
GPN-Star LLR	N/A	3.7
GPN-Star score	N/A	3.5
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	0.0020
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1

Showing 10 of 10 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs7294;

hg19: chr16-31102321;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar