7-138706462-G-A

Position:

• chr7-138706462-G-A

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.*162C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 841,794 control chromosomes in the GnomAD database, including 6,541 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.098 (966 hom., cov: 31)
  • Exomes 𝑓: 0.12 (5575 hom.)
• Consequence: ATP6V0A4 NM_020632.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.44

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=-0.83).
• BP6: Variant 7-138706462-G-A is Benign according to our data. Variant chr7-138706462-G-A is described in ClinVar as [Benign]. Clinvar id is 359000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V0A4	NM_020632.3	c.*162C>T		3_prime_UTR_variant	22/22	ENST00000310018.7	NP_065683.2
ATP6V0A4	NM_130840.3	c.*162C>T		3_prime_UTR_variant	21/21		NP_570855.2
ATP6V0A4	NM_130841.3	c.*162C>T		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.*162C>T		3_prime_UTR_variant	22/22	1	NM_020632.3	ENSP00000308122	P1

Frequencies

GnomAD3 genomes AF: 0.0978 AC: 14867 AN: 152030 Hom.: 966 Cov.: 31

Gnomad AFR AF: 0.0258

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.196

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0415

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.126

GnomAD4 exome AF: 0.117 AC: 80468 AN: 689646 Hom.: 5575 Cov.: 9 AF XY: 0.114 AC XY: 40912 AN XY: 357572

Gnomad4 AFR exome AF: 0.0244

Gnomad4 AMR exome AF: 0.0807

Gnomad4 ASJ exome AF: 0.194

Gnomad4 EAS exome AF: 0.0000320

Gnomad4 SAS exome AF: 0.0412

Gnomad4 FIN exome AF: 0.128

Gnomad4 NFE exome AF: 0.137

Gnomad4 OTH exome AF: 0.117

GnomAD4 genome AF: 0.0977 AC: 14860 AN: 152148 Hom.: 966 Cov.: 31 AF XY: 0.0960 AC XY: 7137 AN XY: 74364

Gnomad4 AFR AF: 0.0257

Gnomad4 AMR AF: 0.116

Gnomad4 ASJ AF: 0.196

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0411

Gnomad4 FIN AF: 0.130

Gnomad4 NFE AF: 0.139

Gnomad4 OTH AF: 0.125

Alfa AF: 0.120 Hom.: 257

Bravo AF: 0.0941

Asia WGS AF: 0.0240 AC: 85 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	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive distal renal tubular acidosis Benign:1

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	-0.83
CADD	Benign	0.51
DANN	Benign	0.59

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: rs55832008; hg19: chr7-138391207;