chr7-138732973-A-G

Position:

• chr7-138732973-A-G

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.1812T>C​(p.His604=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.71 in 1,613,270 control chromosomes in the GnomAD database, including 410,382 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (34209 hom., cov: 30)
  • Exomes 𝑓: 0.72 (376173 hom.)
• Consequence: ATP6V0A4 NM_020632.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0700

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=-0.9).
• BP6: Variant 7-138732973-A-G is Benign according to our data. Variant chr7-138732973-A-G is described in ClinVar as [Benign]. Clinvar id is 261343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-138732973-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.791 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6V0A4	NM_020632.3	c.1812T>C	p.His604=	synonymous_variant	17/22	ENST00000310018.7
ATP6V0A4	NM_130840.3	c.1812T>C	p.His604=	synonymous_variant	16/21
ATP6V0A4	NM_130841.3	c.1812T>C	p.His604=	synonymous_variant	16/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6V0A4	ENST00000310018.7	c.1812T>C	p.His604=	synonymous_variant	17/22	1	NM_020632.3	P1

Frequencies

GnomAD3 genomes AF: 0.660 AC: 100206 AN: 151724 Hom.: 34202 Cov.: 30

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.799

Gnomad AMR AF: 0.759

Gnomad ASJ AF: 0.690

Gnomad EAS AF: 0.812

Gnomad SAS AF: 0.738

Gnomad FIN AF: 0.768

Gnomad MID AF: 0.703

Gnomad NFE AF: 0.717

Gnomad OTH AF: 0.655

GnomAD3 exomes AF: 0.729 AC: 183187 AN: 251388 Hom.: 67755 AF XY: 0.730 AC XY: 99185 AN XY: 135854

Gnomad AFR exome AF: 0.457

Gnomad AMR exome AF: 0.830

Gnomad ASJ exome AF: 0.696

Gnomad EAS exome AF: 0.822

Gnomad SAS exome AF: 0.736

Gnomad FIN exome AF: 0.763

Gnomad NFE exome AF: 0.716

Gnomad OTH exome AF: 0.730

GnomAD4 exome AF: 0.715 AC: 1045437 AN: 1461428 Hom.: 376173 Cov.: 60 AF XY: 0.717 AC XY: 521051 AN XY: 727064

Gnomad4 AFR exome AF: 0.465

Gnomad4 AMR exome AF: 0.822

Gnomad4 ASJ exome AF: 0.691

Gnomad4 EAS exome AF: 0.795

Gnomad4 SAS exome AF: 0.734

Gnomad4 FIN exome AF: 0.763

Gnomad4 NFE exome AF: 0.713

Gnomad4 OTH exome AF: 0.709

GnomAD4 genome AF: 0.660 AC: 100240 AN: 151842 Hom.: 34209 Cov.: 30 AF XY: 0.665 AC XY: 49374 AN XY: 74212

Gnomad4 AFR AF: 0.470

Gnomad4 AMR AF: 0.759

Gnomad4 ASJ AF: 0.690

Gnomad4 EAS AF: 0.812

Gnomad4 SAS AF: 0.739

Gnomad4 FIN AF: 0.768

Gnomad4 NFE AF: 0.717

Gnomad4 OTH AF: 0.651

Alfa AF: 0.702 Hom.: 52487

Bravo AF: 0.653

Asia WGS AF: 0.731 AC: 2541 AN: 3478

EpiCase AF: 0.719

EpiControl AF: 0.727

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Nov 10, 2018	- -

Autosomal recessive distal renal tubular acidosis Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.093
DANN	Benign	0.36

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: rs3807154; hg19: chr7-138417718;