rs1026435

chr7-138734165-G-Achr7-138734165-G-Cchr7-138734165-G-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.1662C>T(p.Phe554=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.716 in 1,612,318 control chromosomes in the GnomAD database, including 414,815 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (37579 hom., cov: 31)
  • Exomes 𝑓: 0.72 (377236 hom.)
• Consequence: ATP6V0A4 NM_020632.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.143

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=-0.78).
• BP6: Variant 7-138734165-G-A is Benign according to our data. Variant chr7-138734165-G-A is described in ClinVar as [Benign]. Clinvar id is 261342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-138734165-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.143 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.782 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6V0A4	NM_020632.3	c.1662C>T	p.Phe554=	synonymous_variant	16/22	ENST00000310018.7
ATP6V0A4	NM_130840.3	c.1662C>T	p.Phe554=	synonymous_variant	15/21
ATP6V0A4	NM_130841.3	c.1662C>T	p.Phe554=	synonymous_variant	15/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6V0A4	ENST00000310018.7	c.1662C>T	p.Phe554=	synonymous_variant	16/22	1	NM_020632.3	P1

Frequencies

GnomAD3 genomes AF: 0.700 AC: 106372 AN: 151886 Hom.: 37569 Cov.: 31

Gnomad AFR AF: 0.620

Gnomad AMI AF: 0.774

Gnomad AMR AF: 0.759

Gnomad ASJ AF: 0.670

Gnomad EAS AF: 0.802

Gnomad SAS AF: 0.721

Gnomad FIN AF: 0.771

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.717

Gnomad OTH AF: 0.676

GnomAD3 exomes AF: 0.734 AC: 184541 AN: 251354 Hom.: 68170 AF XY: 0.731 AC XY: 99346 AN XY: 135836

Gnomad AFR exome AF: 0.611

Gnomad AMR exome AF: 0.826

Gnomad ASJ exome AF: 0.682

Gnomad EAS exome AF: 0.812

Gnomad SAS exome AF: 0.720

Gnomad FIN exome AF: 0.765

Gnomad NFE exome AF: 0.714

Gnomad OTH exome AF: 0.729

GnomAD4 exome AF: 0.718 AC: 1048162 AN: 1460314 Hom.: 377236 Cov.: 55 AF XY: 0.718 AC XY: 521352 AN XY: 726514

Gnomad4 AFR exome AF: 0.616

Gnomad4 AMR exome AF: 0.818

Gnomad4 ASJ exome AF: 0.675

Gnomad4 EAS exome AF: 0.790

Gnomad4 SAS exome AF: 0.720

Gnomad4 FIN exome AF: 0.763

Gnomad4 NFE exome AF: 0.713

Gnomad4 OTH exome AF: 0.715

GnomAD4 genome AF: 0.700 AC: 106427 AN: 152004 Hom.: 37579 Cov.: 31 AF XY: 0.703 AC XY: 52208 AN XY: 74310

Gnomad4 AFR AF: 0.619

Gnomad4 AMR AF: 0.760

Gnomad4 ASJ AF: 0.670

Gnomad4 EAS AF: 0.802

Gnomad4 SAS AF: 0.721

Gnomad4 FIN AF: 0.771

Gnomad4 NFE AF: 0.717

Gnomad4 OTH AF: 0.672

Alfa AF: 0.710 Hom.: 70905

Bravo AF: 0.697

Asia WGS AF: 0.732 AC: 2546 AN: 3478

EpiCase AF: 0.715

EpiControl AF: 0.724

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2019	- -

Autosomal recessive distal renal tubular acidosis Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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	-0.78
Cadd	Benign	0.28
Dann	Benign	0.48

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: rs1026435; hg19: chr7-138418910;