NM_020632.3:c.1155C>T

Variant names:

• chr7-138749192-G-A
• rs58568563
• NM_020632.3:c.1155C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020632.3(ATP6V0A4):​c.1155C>T​(p.Val385Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,613,930 control chromosomes in the GnomAD database, including 1,325 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (548 hom., cov: 31)
  • Exomes 𝑓: 0.0087 (777 hom.)
• Consequence: ATP6V0A4 NM_020632.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -7.11

Genes affected

ATP6V0A4 (HGNC:866): (ATPase H+ transporting V0 subunit a4) This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of intracellular compartments of eukaryotic cells. V-ATPase dependent acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A and three B subunits, two G subunits plus the C, D, E, F, and H subunits. The V1 domain contains the ATP catalytic site. The V0 domain consists of five different subunits: a, c, c', c'', and d. This gene is one of four genes in man and mouse that encode different isoforms of the a subunit. Alternatively spliced transcript variants encoding the same protein have been described. Mutations in this gene are associated with renal tubular acidosis associated with preserved hearing. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 7-138749192-G-A is Benign according to our data. Variant chr7-138749192-G-A is described in ClinVar as [Benign]. Clinvar id is 359019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-7.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6V0A4	NM_020632.3	c.1155C>T	p.Val385Val	synonymous_variant	Exon 12 of 22	ENST00000310018.7	NP_065683.2
ATP6V0A4	NM_130840.3	c.1155C>T	p.Val385Val	synonymous_variant	Exon 11 of 21		NP_570855.2
ATP6V0A4	NM_130841.3	c.1155C>T	p.Val385Val	synonymous_variant	Exon 11 of 21		NP_570856.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6V0A4	ENST00000310018.7	c.1155C>T	p.Val385Val	synonymous_variant	Exon 12 of 22	1	NM_020632.3	ENSP00000308122.2

Frequencies

GnomAD3 genomes AF: 0.0488 AC: 7418 AN: 151942 Hom.: 546 Cov.: 31

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.00851

Gnomad FIN AF: 0.00519

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.0378

GnomAD3 exomes AF: 0.0219 AC: 5510 AN: 251474 Hom.: 354 AF XY: 0.0181 AC XY: 2464 AN XY: 135908

Gnomad AFR exome AF: 0.156

Gnomad AMR exome AF: 0.00711

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.128

Gnomad SAS exome AF: 0.00336

Gnomad FIN exome AF: 0.00554

Gnomad NFE exome AF: 0.000659

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.00872 AC: 12741 AN: 1461870 Hom.: 777 Cov.: 32 AF XY: 0.00811 AC XY: 5898 AN XY: 727240

Gnomad4 AFR exome AF: 0.155

Gnomad4 AMR exome AF: 0.00814

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.129

Gnomad4 SAS exome AF: 0.00372

Gnomad4 FIN exome AF: 0.00470

Gnomad4 NFE exome AF: 0.000334

Gnomad4 OTH exome AF: 0.0184

GnomAD4 genome AF: 0.0489 AC: 7431 AN: 152060 Hom.: 548 Cov.: 31 AF XY: 0.0480 AC XY: 3568 AN XY: 74340

Gnomad4 AFR AF: 0.152

Gnomad4 AMR AF: 0.0145

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.135

Gnomad4 SAS AF: 0.00831

Gnomad4 FIN AF: 0.00519

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.0384

Alfa AF: 0.0220 Hom.: 137

Bravo AF: 0.0541

Asia WGS AF: 0.0740 AC: 257 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Val385Val in exon 12 of ATP6V0A4: This variant is not expected to have clinica l significance because it does not alter an amino acid residue, is not located w ithin the splice consensus sequence, and has been identified in 15.30% (1592/104 06) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exa c.broadinstitute.org; dbSNP rs58568563). -

Autosomal recessive distal renal tubular acidosis Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.82
DANN	Benign	0.59

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

Other links and lift over

dbSNP: rs58568563; hg19: chr7-138433937; COSMIC: COSV59479159; COSMIC: COSV59479159;