Genetic Variant VKORC1L1:c.-99G>C (chr7-65873273-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_173517.6(VKORC1L1):c.-99G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 844,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000053 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

VKORC1L1
NM_173517.6 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.554

Publications

1 publications found

Variant links:

Genes affected

VKORC1L1 (HGNC:21492): (vitamin K epoxide reductase complex subunit 1 like 1) This gene encodes an enzyme important in the vitamin K cycle, which is involved in the carboxylation of glutamate residues present in vitamin K-dependent proteins. The encoded enzyme catalyzes the de-epoxidation of vitamin K 2,3-epoxide. Oxidative stress may upregulate expression of this gene and the encoded protein may protect cells and membrane proteins form oxidative damage. This gene and a related gene (Gene ID: 79001) may have arisen by gene duplication of an ancestral gene. [provided by RefSeq, Oct 2016]

VKORC1L1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13660178).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173517.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VKORC1L1	NM_173517.6	MANE Select	c.-99G>C		5_prime_UTR	Exon 1 of 3	NP_775788.2
	VKORC1L1	NM_001284342.3		c.-99G>C		5_prime_UTR	Exon 1 of 2	NP_001271271.1	Q8N0U8-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VKORC1L1	ENST00000360768.5	TSL:1 MANE Select	c.-99G>C		5_prime_UTR	Exon 1 of 3	ENSP00000353998.2	Q8N0U8-1
VKORC1L1	ENST00000648187.1		c.43G>C	p.Gly15Arg	missense	Exon 1 of 3	ENSP00000497458.1	A0A3B3ISV4
VKORC1L1	ENST00000880558.1		c.-99G>C		5_prime_UTR	Exon 1 of 4	ENSP00000550617.1

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

136050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000828

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000739

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000161

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000533

AC:

AN:

844084

Hom.:

Cov.:

AF XY:

0.0000816

AC XY:

AN XY:

391946

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15980

American (AMR)

AF:

0.00

AC:

AN:

1488

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5578

East Asian (EAS)

AF:

0.000431

AC:

AN:

4636

South Asian (SAS)

AF:

0.000116

AC:

AN:

17294

European-Finnish (FIN)

AF:

0.000470

AC:

AN:

2126

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1694

European-Non Finnish (NFE)

AF:

0.0000495

AC:

AN:

767258

Other (OTH)

AF:

0.0000714

AC:

AN:

28030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.424

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000242

AC:

AN:

136150

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

66202

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000826

AC:

AN:

37538

American (AMR)

AF:

0.0000738

AC:

AN:

13546

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3166

East Asian (EAS)

AF:

0.00

AC:

AN:

4654

South Asian (SAS)

AF:

0.00

AC:

AN:

4418

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7808

Middle Eastern (MID)

AF:

0.00

AC:

AN:

264

European-Non Finnish (NFE)

AF:

0.0000161

AC:

AN:

62036

Other (OTH)

AF:

0.00

AC:

AN:

1884

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.246

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.65

FATHMM_MKL

Benign

0.0022

LIST_S2

Benign

0.34

MetaRNN

Benign

0.14

PhyloP100

-0.55

GERP RS

2.0

PromoterAI

0.016

Neutral

(source)

Mutation Taster

=300/0

polymorphism

(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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over