chr7-138706444-C-A

Variant names:

• chr7-138706444-C-A
• rs1047422453
• NM_020632.3:c.*180G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020632.3(ATP6V0A4):​c.*180G>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 0.0000393 in 712,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: ATP6V0A4 NM_020632.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.113
• Publications: 0 publications found

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]

ATP6V0A4 Gene-Disease associations (from GenCC):

• renal tubular acidosis, distal, 3, with or without sensorineural hearing loss

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal recessive distal renal tubular acidosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020632.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V0A4	NM_020632.3	MANE Select	c.*180G>T		3_prime_UTR	Exon 22 of 22	NP_065683.2	Q9HBG4
	ATP6V0A4	NM_130840.3		c.*180G>T		3_prime_UTR	Exon 21 of 21	NP_570855.2	Q9HBG4
	ATP6V0A4	NM_130841.3		c.*180G>T		3_prime_UTR	Exon 21 of 21	NP_570856.2	Q9HBG4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V0A4	ENST00000310018.7	TSL:1 MANE Select	c.*180G>T		3_prime_UTR	Exon 22 of 22	ENSP00000308122.2	Q9HBG4
	ATP6V0A4	ENST00000393054.5	TSL:5	c.*180G>T		3_prime_UTR	Exon 21 of 21	ENSP00000376774.1	Q9HBG4
	ATP6V0A4	ENST00000645515.1		c.*180G>T		3_prime_UTR	Exon 22 of 22	ENSP00000496421.1	Q9HBG4

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152126 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000411 AC: 23 AN: 559902 Hom.: 0 Cov.: 7 AF XY: 0.0000375 AC XY: 11 AN XY: 293272

African (AFR) AF: 0.00 AC: 0 AN: 15392

American (AMR) AF: 0.00 AC: 0 AN: 28624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16520

East Asian (EAS) AF: 0.00 AC: 0 AN: 30496

South Asian (SAS) AF: 0.00 AC: 0 AN: 54508

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2238

European-Non Finnish (NFE) AF: 0.0000626 AC: 22 AN: 351672

Other (OTH) AF: 0.0000337 AC: 1 AN: 29640

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152126 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74314

African (AFR) AF: 0.00 AC: 0 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000529

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive distal renal tubular acidosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.1
DANN	Benign	0.67
PhyloP100		0.11

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

Other links and lift over

dbSNP: rs1047422453; hg19: chr7-138391189;