rs150777839

Positions:

• chr7-138722001-C-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_020632.3(ATP6V0A4):​c.2035G>T​(p.Asp679Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00666 in 1,614,168 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (52 hom.)
• Consequence: ATP6V0A4 NM_020632.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.222

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0078112483).
• BP6: Variant 7-138722001-C-A is Benign according to our data. Variant chr7-138722001-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 261344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V0A4	NM_020632.3	c.2035G>T	p.Asp679Tyr	missense_variant	19/22	ENST00000310018.7	NP_065683.2
ATP6V0A4	NM_130840.3	c.2035G>T	p.Asp679Tyr	missense_variant	18/21		NP_570855.2
ATP6V0A4	NM_130841.3	c.2035G>T	p.Asp679Tyr	missense_variant	18/21		NP_570856.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V0A4	ENST00000310018.7	c.2035G>T	p.Asp679Tyr	missense_variant	19/22	1	NM_020632.3	ENSP00000308122.2

Frequencies

GnomAD3 genomes AF: 0.00517 AC: 787 AN: 152182 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.0205

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00750

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.00606 AC: 1523 AN: 251434 Hom.: 13 AF XY: 0.00656 AC XY: 891 AN XY: 135890

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00599

Gnomad ASJ exome AF: 0.0198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00670

Gnomad FIN exome AF: 0.000970

Gnomad NFE exome AF: 0.00724

Gnomad OTH exome AF: 0.00733

GnomAD4 exome AF: 0.00681 AC: 9962 AN: 1461868 Hom.: 52 Cov.: 31 AF XY: 0.00694 AC XY: 5050 AN XY: 727242

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.00622

Gnomad4 ASJ exome AF: 0.0209

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00693

Gnomad4 FIN exome AF: 0.00131

Gnomad4 NFE exome AF: 0.00709

Gnomad4 OTH exome AF: 0.00783

GnomAD4 genome AF: 0.00517 AC: 788 AN: 152300 Hom.: 6 Cov.: 32 AF XY: 0.00500 AC XY: 372 AN XY: 74468

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.00576

Gnomad4 ASJ AF: 0.0205

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00750

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00804 Hom.: 8

Bravo AF: 0.00528

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00674 AC: 58

ExAC AF: 0.00566 AC: 687

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00943

EpiControl AF: 0.00812

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2020	This variant is associated with the following publications: (PMID: 24252324, 28233610, 16611712, 27884173) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	ATP6V0A4: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	Variant summary: ATP6V0A4 c.2035G>T (p.Asp679Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0061 in 251434 control chromosomes in the gnomAD database, including 13 homozygotes. The observed variant frequency is approximately 5.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATP6V0A4 causing Renal Tubular Acidosis, Distal, Autosomal Recessive phenotype (0.0011), strongly suggesting that the variant is benign. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Autosomal recessive distal renal tubular acidosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.43	T;T;T;.;.;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.59	.;T;.;T;T;.
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.0078	T;T;T;T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.3	L;L;L;.;.;L
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.2	N;N;.;.;.;N
REVEL	Uncertain	0.58
Sift	Uncertain	0.010	D;D;.;.;.;D
Sift4G	Uncertain	0.026	D;D;.;.;.;D
Polyphen		0.60	P;P;P;.;.;P
Vest4		0.31
MVP		0.75
MPC		0.34
ClinPred		0.016	T
GERP RS		-2.4
Varity_R		0.071
gMVP		0.42

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: rs150777839; hg19: chr7-138406746; COSMIC: COSV59476036;