5-133975936-C-T

Variant names:

• chr5-133975936-C-T
• NM_003374.3:c.637G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003374.3(VDAC1):​c.637G>A​(p.Gly213Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: VDAC1 NM_003374.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.87
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003374.3. 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
	VDAC1	NM_003374.3	MANE Select	c.637G>A	p.Gly213Arg	missense	Exon 7 of 9	NP_003365.1	P21796
	VDAC1	NM_001401028.1		c.679G>A	p.Gly227Arg	missense	Exon 8 of 10	NP_001387957.1
	VDAC1	NM_001401008.1		c.637G>A	p.Gly213Arg	missense	Exon 8 of 10	NP_001387937.1	A0A1L1UHR1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDAC1	ENST00000265333.8	TSL:2 MANE Select	c.637G>A	p.Gly213Arg	missense	Exon 7 of 9	ENSP00000265333.3	P21796
	VDAC1	ENST00000395044.7	TSL:1	c.637G>A	p.Gly213Arg	missense	Exon 7 of 9	ENSP00000378484.3	P21796
	VDAC1	ENST00000395047.6	TSL:1	c.637G>A	p.Gly213Arg	missense	Exon 7 of 9	ENSP00000378487.2	P21796

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461676 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727142

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5624

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.094	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.82	P
Vest4		0.88
MutPred		0.70		Gain of MoRF binding (P = 0.0213)
MVP		0.47
MPC		1.7
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.84
gMVP		0.57
Mutation Taster		=1/99	disease causing

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

Other links and lift over

hg19: chr5-133311627;