rs8050894

Variant names:

Your query was ambiguous. Multiple possible variants found:

Germline classification Cancer classification (beta)

Variant summary

Our verdict is . The variant received -12 ACMG points: 0P and 12B. BA1BP4_Strong

The NM_024006.6(VKORC1):c.283+124G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.391 (AC=401,127) in the gnomAD database across 1,025,128 control chromosomes, including 86,595 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.896. 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 0.38 ( 11456 hom., cov: 28)

Exomes 𝑓: 0.39 ( 75139 hom. )

Consequence

VKORC1
NM_024006.6 intron

Scores

Clinical Significance

drug response reviewed by expert panel B:1O:1

Conservation

PhyloP100: -0.576

Publications

116 publications found

Variant links:

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, Labcorp Genetics (formerly Invitae), PanelApp Australia
vitamin K-dependent clotting factors, combined deficiency of, type 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

VKORC1 links:

ENSG00000255439 (HGNC:):

ENSG00000255439 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_024006.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG 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 = 0.8963 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

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

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VKORC1	NM_024006.6	MANE Select	c.283+124G>C	intron	N/A	NP_076869.1	Q9BQB6-1
VKORC1	NM_001311311.2		c.283+124G>C	intron	N/A	NP_001298240.1
VKORC1	NM_206824.3		c.173+1369G>C	intron	N/A	NP_996560.1	Q9BQB6-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VKORC1	ENST00000394975.3	TSL:1 MANE Select	c.283+124G>C	intron	N/A	ENSP00000378426.2	Q9BQB6-1
ENSG00000255439	ENST00000529564.1	TSL:4	c.283+124G>C	intron	N/A	ENSP00000431371.1	E9PLN8
VKORC1	ENST00000319788.11	TSL:1	c.283+124G>C	intron	N/A	ENSP00000326135.7	Q9BQB6-2

Frequencies

GnomAD3 genomes

AF:

0.377

AC:

55851

AN:

148126

Hom.:

11456

Cov.:

show subpopulations

Gnomad AFR

AF:

0.271

Gnomad AMI

AF:

0.491

Gnomad AMR

AF:

0.429

Gnomad ASJ

AF:

0.498

Gnomad EAS

AF:

0.894

Gnomad SAS

AF:

0.193

Gnomad FIN

AF:

0.414

Gnomad MID

AF:

0.556

Gnomad NFE

AF:

0.386

Gnomad OTH

AF:

0.438

GnomAD4 exome

AF:

0.394

AC:

345271

AN:

876912

Hom.:

75139

AF XY:

0.386

AC XY:

172679

AN XY:

446832

show subpopulations

African (AFR)

AF:

0.261

AC:

5925

AN:

22706

American (AMR)

AF:

0.463

AC:

15835

AN:

34188

Ashkenazi Jewish (ASJ)

AF:

0.485

AC:

9720

AN:

20040

East Asian (EAS)

AF:

0.905

AC:

30789

AN:

34028

South Asian (SAS)

AF:

0.193

AC:

12504

AN:

64762

European-Finnish (FIN)

AF:

0.391

AC:

12917

AN:

33068

Middle Eastern (MID)

AF:

0.514

AC:

1527

AN:

2972

European-Non Finnish (NFE)

AF:

0.383

AC:

239345

AN:

624188

Other (OTH)

AF:

0.408

AC:

16709

AN:

40960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

9787

19575

29362

39150

48937

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5918

11836

17754

23672

29590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.377

AC:

55856

AN:

148216

Hom.:

11456

Cov.:

AF XY:

0.378

AC XY:

27288

AN XY:

72154

show subpopulations

African (AFR)

AF:

0.271

AC:

10859

AN:

40084

American (AMR)

AF:

0.429

AC:

6289

AN:

14656

Ashkenazi Jewish (ASJ)

AF:

0.498

AC:

1717

AN:

3450

East Asian (EAS)

AF:

0.894

AC:

4572

AN:

5112

South Asian (SAS)

AF:

0.193

AC:

877

AN:

4534

European-Finnish (FIN)

AF:

0.414

AC:

4068

AN:

9820

Middle Eastern (MID)

AF:

0.567

AC:

161

AN:

284

European-Non Finnish (NFE)

AF:

0.386

AC:

25960

AN:

67294

Other (OTH)

AF:

0.437

AC:

908

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1667

3334

5000

6667

8334

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

516

1032

1548

2064

2580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.383

Hom.:

6711

Bravo

AF:

0.381

Asia WGS

AF:

0.470

AC:

1638

AN:

3478

Local populations

Turkish Variome

AF:

0.481

AC:

744

AN:

1546

Hom.:

184

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.907

AC:

8124

AN:

8960

Hom.:

3693

ABraOM SABE-WGS-1171

AF:

0.421

AC:

986

AN:

2342

Hom.:

223

ClinVar

ClinVar submissions

Significance:drug response

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

warfarin response - Dosage (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.72

(source)

DANN

Benign

0.66

PhyloP100

-0.58

PromoterAI

-0.022

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over