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: 202 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

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

• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
• BA1: 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	NP_076869.1	A0A0S2Z6I4
	VKORC1	NM_001311311.2		c.*134G>A		3_prime_UTR	Exon 4 of 4	NP_001298240.1
	VKORC1	NM_206824.3		c.*237G>A		3_prime_UTR	Exon 2 of 2	NP_996560.1	Q9BQB6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VKORC1	ENST00000394975.3	TSL:1 MANE Select	c.*134G>A		3_prime_UTR	Exon 3 of 3	ENSP00000378426.2	Q9BQB6-1
	VKORC1	ENST00000319788.11	TSL:1	c.*237G>A		3_prime_UTR	Exon 4 of 4	ENSP00000326135.7	Q9BQB6-2
	VKORC1	ENST00000354895.4	TSL:1	c.*237G>A		3_prime_UTR	Exon 2 of 2	ENSP00000346969.4	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	0.403	61172	12858	151832	31
GnomAD4 exome	0.390	496903	102978	1274084	19
GnomAD4 genome	0.403	61257	12893	151950	31
TOPMed (Bravo)	0.395	104469	21423	264690
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	0.382	232770	45947	609240
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	0.358	838	158	2342
ChinaMAP Phase 1	0.0897
Denmark Genome	0.377	113		300
GenomeAsia100K	0.458	1591		3478
Korea4K (4,157 Koreans)	0.0740	533		7234
Qatari Genome	0.347	61		176
ToMMo 61KJPN (+60KJPN MNV)	0.0913	11167	506	122326
Turkish Variome	0.320	495	81	1546
UK10K	0.380	2873		7562
WBBC (Westlake BioBank for Chinese) pilot	0.0906	812	43	8960

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 prediction	Prediction	Score
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	polymorphism (auto)	100/0
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 prediction	Prediction	Score
Pangolin (max)	Benign	-	0.0
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.0

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.

Other links and lift over

dbSNP: rs7294;

hg19: chr16-31102321;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar