7-138706513-G-T

Position:

• chr7-138706513-G-T

Variant summary

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

The NM_020632.3(ATP6V0A4):​c.*111C>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 0.00697 in 1,296,138 control chromosomes in the GnomAD database, including 508 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (315 hom., cov: 31)
  • Exomes 𝑓: 0.0036 (193 hom.)
• Consequence: ATP6V0A4 NM_020632.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0670

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=-0.82).
• BP6: Variant 7-138706513-G-T is Benign according to our data. Variant chr7-138706513-G-T is described in ClinVar as [Benign]. Clinvar id is 359001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V0A4	NM_020632.3	c.*111C>A		3_prime_UTR_variant	22/22	ENST00000310018.7	NP_065683.2
ATP6V0A4	NM_130840.3	c.*111C>A		3_prime_UTR_variant	21/21		NP_570855.2
ATP6V0A4	NM_130841.3	c.*111C>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.*111C>A		3_prime_UTR_variant	22/22	1	NM_020632.3	ENSP00000308122	P1

Frequencies

GnomAD3 genomes AF: 0.0325 AC: 4941 AN: 151976 Hom.: 314 Cov.: 31

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.0264

GnomAD4 exome AF: 0.00357 AC: 4088 AN: 1144044 Hom.: 193 Cov.: 15 AF XY: 0.00306 AC XY: 1764 AN XY: 576820

Gnomad4 AFR exome AF: 0.117

Gnomad4 AMR exome AF: 0.00731

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000225

Gnomad4 FIN exome AF: 0.0000237

Gnomad4 NFE exome AF: 0.000222

Gnomad4 OTH exome AF: 0.00905

GnomAD4 genome AF: 0.0325 AC: 4946 AN: 152094 Hom.: 315 Cov.: 31 AF XY: 0.0320 AC XY: 2380 AN XY: 74372

Gnomad4 AFR AF: 0.113

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.0261

Alfa AF: 0.00174 Hom.: 1

Bravo AF: 0.0375

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 07, 2020

- -

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	-0.82
CADD	Benign	1.0
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs75920897; hg19: chr7-138391258;