7-138706385-C-T

Position:

• chr7-138706385-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000310018.7(ATP6V0A4):​c.*239G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 529,434 control chromosomes in the GnomAD database, including 11,700 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4041 hom., cov: 31)
  • Exomes 𝑓: 0.19 (7659 hom.)
• Consequence: ATP6V0A4 ENST00000310018.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.659

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 7-138706385-C-T is Benign according to our data. Variant chr7-138706385-C-T is described in ClinVar as [Benign]. Clinvar id is 358999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V0A4	NM_020632.3	c.*239G>A		3_prime_UTR_variant	22/22	ENST00000310018.7	NP_065683.2
ATP6V0A4	NM_130840.3	c.*239G>A		3_prime_UTR_variant	21/21		NP_570855.2
ATP6V0A4	NM_130841.3	c.*239G>A		3_prime_UTR_variant	21/21		NP_570856.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V0A4	ENST00000310018.7	c.*239G>A		3_prime_UTR_variant	22/22	1	NM_020632.3	ENSP00000308122	P1

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33765 AN: 151998 Hom.: 4035 Cov.: 31

Gnomad AFR AF: 0.299

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.0484

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.242

GnomAD4 exome AF: 0.193 AC: 72706 AN: 377318 Hom.: 7659 Cov.: 3 AF XY: 0.195 AC XY: 38713 AN XY: 198736

Gnomad4 AFR exome AF: 0.305

Gnomad4 AMR exome AF: 0.152

Gnomad4 ASJ exome AF: 0.269

Gnomad4 EAS exome AF: 0.0607

Gnomad4 SAS exome AF: 0.219

Gnomad4 FIN exome AF: 0.172

Gnomad4 NFE exome AF: 0.196

Gnomad4 OTH exome AF: 0.202

GnomAD4 genome AF: 0.222 AC: 33776 AN: 152116 Hom.: 4041 Cov.: 31 AF XY: 0.221 AC XY: 16425 AN XY: 74372

Gnomad4 AFR AF: 0.299

Gnomad4 AMR AF: 0.197

Gnomad4 ASJ AF: 0.279

Gnomad4 EAS AF: 0.0484

Gnomad4 SAS AF: 0.215

Gnomad4 FIN AF: 0.188

Gnomad4 NFE AF: 0.197

Gnomad4 OTH AF: 0.240

Alfa AF: 0.206 Hom.: 1886

Bravo AF: 0.225

Asia WGS AF: 0.141 AC: 493 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Autosomal recessive distal renal tubular acidosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.75
CADD	Benign	3.6
DANN	Benign	0.75

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: rs8846; hg19: chr7-138391130;