NM_020632.3:c.1478+17A>G

Variant names:

• chr7-138745106-T-C
• rs6467797
• NM_020632.3:c.1478+17A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020632.3(ATP6V0A4):​c.1478+17A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 1,603,716 control chromosomes in the GnomAD database, including 31,139 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (6143 hom., cov: 32)
  • Exomes 𝑓: 0.18 (24996 hom.)
• Consequence: ATP6V0A4 NM_020632.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.210
• Publications: 10 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 7-138745106-T-C is Benign according to our data. Variant chr7-138745106-T-C is described in ClinVar as Benign. ClinVar VariationId is 261341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

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.1478+17A>G		intron	N/A	NP_065683.2	Q9HBG4
	ATP6V0A4	NM_130840.3		c.1478+17A>G		intron	N/A	NP_570855.2	Q9HBG4
	ATP6V0A4	NM_130841.3		c.1478+17A>G		intron	N/A	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.1478+17A>G		intron	N/A	ENSP00000308122.2	Q9HBG4
	ATP6V0A4	ENST00000353492.4	TSL:1	c.1478+17A>G		intron	N/A	ENSP00000253856.6	Q9HBG4
	ATP6V0A4	ENST00000393054.5	TSL:5	c.1478+17A>G		intron	N/A	ENSP00000376774.1	Q9HBG4

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38620 AN: 152068 Hom.: 6116 Cov.: 32

Gnomad AFR AF: 0.452

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.275

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.231

GnomAD2 exomes AF: 0.189 AC: 47469 AN: 251436 AF XY: 0.183

Gnomad AFR exome AF: 0.460

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.192

Gnomad EAS exome AF: 0.288

Gnomad FIN exome AF: 0.172

Gnomad NFE exome AF: 0.178

Gnomad OTH exome AF: 0.190

GnomAD4 exome AF: 0.177 AC: 256840 AN: 1451530 Hom.: 24996 Cov.: 32 AF XY: 0.176 AC XY: 126863 AN XY: 722798

African (AFR) AF: 0.471 AC: 15626 AN: 33196

American (AMR) AF: 0.107 AC: 4801 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 4833 AN: 26082

East Asian (EAS) AF: 0.258 AC: 10240 AN: 39628

South Asian (SAS) AF: 0.133 AC: 11416 AN: 86036

European-Finnish (FIN) AF: 0.170 AC: 9072 AN: 53404

Middle Eastern (MID) AF: 0.204 AC: 1167 AN: 5720

European-Non Finnish (NFE) AF: 0.170 AC: 187722 AN: 1102682

Other (OTH) AF: 0.199 AC: 11963 AN: 60084

GnomAD4 genome AF: 0.254 AC: 38687 AN: 152186 Hom.: 6143 Cov.: 32 AF XY: 0.251 AC XY: 18690 AN XY: 74386

African (AFR) AF: 0.453 AC: 18777 AN: 41490

American (AMR) AF: 0.160 AC: 2443 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 614 AN: 3472

East Asian (EAS) AF: 0.275 AC: 1425 AN: 5184

South Asian (SAS) AF: 0.139 AC: 673 AN: 4826

European-Finnish (FIN) AF: 0.181 AC: 1918 AN: 10596

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.178 AC: 12083 AN: 68010

Other (OTH) AF: 0.232 AC: 491 AN: 2116

Alfa AF: 0.207 Hom.: 8130

Bravo AF: 0.265

Asia WGS AF: 0.247 AC: 857 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Autosomal recessive distal renal tubular acidosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.7
DANN	Benign	0.45
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism (auto)

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: rs6467797; hg19: chr7-138429851; COSMIC: COSV59479179;