Genetic Variant VDAC1:p.Thr55Met (chr5-133991108-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001401029.1(VDAC1):c.-168C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000342 in 1,461,312 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000034 ( 1 hom. )

Consequence

VDAC1
NM_001401029.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.27

Publications

1 publications found

Variant links:

Genes affected

VDAC1 (HGNC:12669): (voltage dependent anion channel 1) This gene encodes a voltage-dependent anion channel protein that is a major component of the outer mitochondrial membrane. The encoded protein facilitates the exchange of metabolites and ions across the outer mitochondrial membrane and may regulate mitochondrial functions. This protein also forms channels in the plasma membrane and may be involved in transmembrane electron transport. Alternate splicing results in multiple transcript variants. Multiple pseudogenes of this gene are found on chromosomes 1, 2 3, 6, 9, 12, X and Y.[provided by RefSeq, Sep 2010]

VDAC1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1290147).

BS2

High AC in GnomAdExome4 at 50 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001401029.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VDAC1	NM_003374.3	MANE Select	c.164C>T	p.Thr55Met	missense	Exon 4 of 9	NP_003365.1	P21796
VDAC1	NM_001401029.1		c.-168C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 8	NP_001387958.1
VDAC1	NM_001401031.1		c.-210C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 8	NP_001387960.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VDAC1	ENST00000265333.8	TSL:2 MANE Select	c.164C>T	p.Thr55Met	missense	Exon 4 of 9	ENSP00000265333.3	P21796
VDAC1	ENST00000395044.7	TSL:1	c.164C>T	p.Thr55Met	missense	Exon 4 of 9	ENSP00000378484.3	P21796
VDAC1	ENST00000395047.6	TSL:1	c.164C>T	p.Thr55Met	missense	Exon 4 of 9	ENSP00000378487.2	P21796

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000757

AC:

AN:

250944

AF XY:

0.000103

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000342

AC:

AN:

1461312

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

727012

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000406

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52856

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1112002

Other (OTH)

AF:

0.0000331

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

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

Cov.:

Alfa

AF:

0.0000568

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000741

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

Eigen

Benign

0.13

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.74

M_CAP

Benign

0.010

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

PhyloP100

3.3

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.80

REVEL

Benign

0.054

Sift

Benign

0.21

Sift4G

Benign

0.20

Polyphen

0.76

Vest4

0.42

MutPred

0.24

Loss of phosphorylation at T55 (P = 0.0518)

MVP

0.15

MPC

1.1

ClinPred

0.13

GERP RS

5.0

Varity_R

0.047

gMVP

0.29

Mutation Taster

=88/12

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over