Variant 8-42394269-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The ENST00000022615.9(VDAC3):c.58A>C(p.Lys20Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,156 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

VDAC3
ENST00000022615.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.03

Variant links:

Genes affected

VDAC3 (HGNC:12674): (voltage dependent anion channel 3) This gene encodes a voltage-dependent anion channel (VDAC), and belongs to the mitochondrial porin family. VDACs are small, integral membrane proteins that traverse the outer mitochondrial membrane and conduct ATP and other small metabolites. They are known to bind several kinases of intermediary metabolism, thought to be involved in translocation of adenine nucleotides, and are hypothesized to form part of the mitochondrial permeability transition pore, which results in the release of cytochrome c at the onset of apoptotic cell death. Alternatively transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Oct 2011]

VDAC3 links:

VDAC3 (HGNC:):

VDAC3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a modified_residue N6-acetyllysine (size 0) in uniprot entity VDAC3_HUMAN

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VDAC3	NM_005662.7 linkuse as main transcript	c.58A>C	p.Lys20Gln	missense_variant	3/10	ENST00000022615.9	NP_005653.3	Q9Y277-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VDAC3	ENST00000022615.9 linkuse as main transcript	c.58A>C	p.Lys20Gln	missense_variant	3/10	1	NM_005662.7	ENSP00000022615.4		Q9Y277-1
VDAC3	ENST00000518495.5 linkuse as main transcript	n.58A>C		non_coding_transcript_exon_variant	3/8	3		ENSP00000430373.1		E5RFL1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461156

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726910

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000547

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2024

The c.58A>C (p.K20Q) alteration is located in exon 3 (coding exon 1) of the VDAC3 gene. This alteration results from a A to C substitution at nucleotide position 58, causing the lysine (K) at amino acid position 20 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.64

.;.;.;.;D

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

D;D;D;D;D

M_CAP

Benign

0.041

MetaRNN

Uncertain

0.71

D;D;D;D;D

MetaSVM

Benign

-0.34

MutationAssessor

Pathogenic

3.2

.;.;.;M;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-3.7

D;D;D;D;D

REVEL

Uncertain

0.40

Sift

Benign

0.035

D;D;D;D;D

Sift4G

Uncertain

0.044

D;D;D;D;D

Polyphen

0.64

.;.;.;.;P

Vest4

0.85, 0.84, 0.84

MutPred

0.72

Loss of methylation at K20 (P = 0.0089);Loss of methylation at K20 (P = 0.0089);Loss of methylation at K20 (P = 0.0089);Loss of methylation at K20 (P = 0.0089);Loss of methylation at K20 (P = 0.0089);

MVP

0.44

MPC

0.80

ClinPred

0.99

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.57

gMVP

0.78

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over