chr7-138749192-G-A

Variant names:

• chr7-138749192-G-A
• rs58568563
• NM_020632.3:c.1155C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020632.3(ATP6V0A4):​c.1155C>T​(p.Val385Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,613,930 control chromosomes in the GnomAD database, including 1,325 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (548 hom., cov: 31)
  • Exomes 𝑓: 0.0087 (777 hom.)
• Consequence: ATP6V0A4 NM_020632.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -7.11
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 7-138749192-G-A is Benign according to our data. Variant chr7-138749192-G-A is described in ClinVar as Benign. ClinVar VariationId is 359019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-7.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.149 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.1155C>T	p.Val385Val	synonymous	Exon 12 of 22	NP_065683.2	Q9HBG4
	ATP6V0A4	NM_130840.3		c.1155C>T	p.Val385Val	synonymous	Exon 11 of 21	NP_570855.2	Q9HBG4
	ATP6V0A4	NM_130841.3		c.1155C>T	p.Val385Val	synonymous	Exon 11 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.1155C>T	p.Val385Val	synonymous	Exon 12 of 22	ENSP00000308122.2	Q9HBG4
	ATP6V0A4	ENST00000353492.4	TSL:1	c.1155C>T	p.Val385Val	synonymous	Exon 11 of 21	ENSP00000253856.6	Q9HBG4
	ATP6V0A4	ENST00000393054.5	TSL:5	c.1155C>T	p.Val385Val	synonymous	Exon 11 of 21	ENSP00000376774.1	Q9HBG4

Frequencies

GnomAD3 genomes AF: 0.0488 AC: 7418 AN: 151942 Hom.: 546 Cov.: 31

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.00851

Gnomad FIN AF: 0.00519

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.0378

GnomAD2 exomes AF: 0.0219 AC: 5510 AN: 251474 AF XY: 0.0181

Gnomad AFR exome AF: 0.156

Gnomad AMR exome AF: 0.00711

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.128

Gnomad FIN exome AF: 0.00554

Gnomad NFE exome AF: 0.000659

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.00872 AC: 12741 AN: 1461870 Hom.: 777 Cov.: 32 AF XY: 0.00811 AC XY: 5898 AN XY: 727240

African (AFR) AF: 0.155 AC: 5175 AN: 33474

American (AMR) AF: 0.00814 AC: 364 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26134

East Asian (EAS) AF: 0.129 AC: 5116 AN: 39700

South Asian (SAS) AF: 0.00372 AC: 321 AN: 86256

European-Finnish (FIN) AF: 0.00470 AC: 251 AN: 53418

Middle Eastern (MID) AF: 0.00468 AC: 27 AN: 5766

European-Non Finnish (NFE) AF: 0.000334 AC: 371 AN: 1112006

Other (OTH) AF: 0.0184 AC: 1112 AN: 60392

GnomAD4 genome AF: 0.0489 AC: 7431 AN: 152060 Hom.: 548 Cov.: 31 AF XY: 0.0480 AC XY: 3568 AN XY: 74340

African (AFR) AF: 0.152 AC: 6287 AN: 41428

American (AMR) AF: 0.0145 AC: 222 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.135 AC: 697 AN: 5168

South Asian (SAS) AF: 0.00831 AC: 40 AN: 4814

European-Finnish (FIN) AF: 0.00519 AC: 55 AN: 10588

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000676 AC: 46 AN: 68014

Other (OTH) AF: 0.0384 AC: 81 AN: 2110

Alfa AF: 0.0232 Hom.: 209

Bravo AF: 0.0541

Asia WGS AF: 0.0740 AC: 257 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Autosomal recessive distal renal tubular acidosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.82
DANN	Benign	0.59
PhyloP100		-7.1
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: rs58568563; hg19: chr7-138433937; COSMIC: COSV59479159; COSMIC: COSV59479159;