16-31091000-C-G

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Moderate

The NM_024006.6(VKORC1):c.*134G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: VKORC1 NM_024006.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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 ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])

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

VKORC1 NM_024006.6

MANE Select

HGVSc / HGVSpc.*134G>C

Exon rankExon 3 of 3

3_prime_UTR

Prot: NP_076869.1UniProt: A0A0S2Z6I4Q9BQB6-1

VKORC1 NM_001311311.2

HGVSc / HGVSpc.*134G>C

Exon rankExon 4 of 4

3_prime_UTR

Prot: NP_001298240.1

VKORC1 NM_206824.3

HGVSc / HGVSpc.*237G>C

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>C	3_prime_UTR	Exon 3 of 3	Prot: ENSP00000378426.2 UniProt:
	VKORC1 ENST00000319788.11	TSL:1	c.*237G>C	3_prime_UTR	Exon 4 of 4	Prot: ENSP00000326135.7 UniProt:
	VKORC1 ENST00000354895.4	TSL:1	c.*237G>C	3_prime_UTR	Exon 2 of 2	Prot: ENSP00000346969.4 UniProt:

VKORC1 ENST00000394975.3

TSL:1MANE Select

HGVSc / HGVSpc.*134G>C

Exon rankExon 3 of 3

3_prime_UTR

Prot: ENSP00000378426.2UniProt: Q9BQB6-1

VKORC1 ENST00000319788.11

TSL:1

HGVSc / HGVSpc.*237G>C

Exon rankExon 4 of 4

3_prime_UTR

Prot: ENSP00000326135.7UniProt: Q9BQB6-2

VKORC1 ENST00000354895.4

TSL:1

HGVSc / HGVSpc.*237G>C

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:19
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:31

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	6.9
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.3
DANN	Benign	0.42
GPN-Star LLR	N/A	0.94
GPN-Star score	N/A	-0.94
PhyloP100	Benign	0.0020

Showing 7 of 7 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