7-138706551-G-A

Position:

• chr7-138706551-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_020632.3(ATP6V0A4):​c.*73C>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 0.00202 in 1,562,486 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0041 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0018 (49 hom.)
• Consequence: ATP6V0A4 NM_020632.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.125

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 7-138706551-G-A is Benign according to our data. Variant chr7-138706551-G-A is described in ClinVar as [Benign]. Clinvar id is 359002.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00411 (625/152174) while in subpopulation SAS AF= 0.027 (130/4818). AF 95% confidence interval is 0.0232. There are 7 homozygotes in gnomad4. There are 309 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V0A4	NM_020632.3	c.*73C>T		3_prime_UTR_variant	22/22	ENST00000310018.7	NP_065683.2
ATP6V0A4	NM_130840.3	c.*73C>T		3_prime_UTR_variant	21/21		NP_570855.2
ATP6V0A4	NM_130841.3	c.*73C>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.*73C>T		3_prime_UTR_variant	22/22	1	NM_020632.3	ENSP00000308122	P1

Frequencies

GnomAD3 genomes AF: 0.00410 AC: 623 AN: 152056 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.0115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0270

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000959

GnomAD4 exome AF: 0.00180 AC: 2534 AN: 1410312 Hom.: 49 Cov.: 26 AF XY: 0.00236 AC XY: 1663 AN XY: 704018

Gnomad4 AFR exome AF: 0.0109

Gnomad4 AMR exome AF: 0.000822

Gnomad4 ASJ exome AF: 0.000273

Gnomad4 EAS exome AF: 0.0000765

Gnomad4 SAS exome AF: 0.0230

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000215

Gnomad4 OTH exome AF: 0.00258

GnomAD4 genome AF: 0.00411 AC: 625 AN: 152174 Hom.: 7 Cov.: 31 AF XY: 0.00415 AC XY: 309 AN XY: 74406

Gnomad4 AFR AF: 0.0115

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0270

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.00229 Hom.: 0

Bravo AF: 0.00375

Asia WGS AF: 0.0130 AC: 44 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	0.65
DANN	Benign	0.57

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: rs78419825; hg19: chr7-138391296;