chr7-138722001-C-A

Variant names:

• chr7-138722001-C-A
• rs150777839
• NM_020632.3:c.2035G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020632.3(ATP6V0A4):​c.2035G>T​(p.Asp679Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00666 in 1,614,168 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (52 hom.)
• Consequence: ATP6V0A4 NM_020632.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.222
• Publications: 12 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 (MetaRNN=0.0078112483).
• BP6: Variant 7-138722001-C-A is Benign according to our data. Variant chr7-138722001-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00517 (788/152300) while in subpopulation NFE AF = 0.0075 (510/68024). AF 95% confidence interval is 0.00696. There are 6 homozygotes in GnomAd4. There are 372 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.2035G>T	p.Asp679Tyr	missense	Exon 19 of 22	NP_065683.2	Q9HBG4
	ATP6V0A4	NM_130840.3		c.2035G>T	p.Asp679Tyr	missense	Exon 18 of 21	NP_570855.2	Q9HBG4
	ATP6V0A4	NM_130841.3		c.2035G>T	p.Asp679Tyr	missense	Exon 18 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.2035G>T	p.Asp679Tyr	missense	Exon 19 of 22	ENSP00000308122.2	Q9HBG4
	ATP6V0A4	ENST00000353492.4	TSL:1	c.2035G>T	p.Asp679Tyr	missense	Exon 18 of 21	ENSP00000253856.6	Q9HBG4
	ATP6V0A4	ENST00000393054.5	TSL:5	c.2035G>T	p.Asp679Tyr	missense	Exon 18 of 21	ENSP00000376774.1	Q9HBG4

Frequencies

GnomAD3 genomes AF: 0.00517 AC: 787 AN: 152182 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.0205

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00750

Gnomad OTH AF: 0.00861

GnomAD2 exomes AF: 0.00606 AC: 1523 AN: 251434 AF XY: 0.00656

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00599

Gnomad ASJ exome AF: 0.0198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000970

Gnomad NFE exome AF: 0.00724

Gnomad OTH exome AF: 0.00733

GnomAD4 exome AF: 0.00681 AC: 9962 AN: 1461868 Hom.: 52 Cov.: 31 AF XY: 0.00694 AC XY: 5050 AN XY: 727242

African (AFR) AF: 0.00122 AC: 41 AN: 33480

American (AMR) AF: 0.00622 AC: 278 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0209 AC: 547 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00693 AC: 598 AN: 86256

European-Finnish (FIN) AF: 0.00131 AC: 70 AN: 53418

Middle Eastern (MID) AF: 0.0130 AC: 75 AN: 5766

European-Non Finnish (NFE) AF: 0.00709 AC: 7880 AN: 1112002

Other (OTH) AF: 0.00783 AC: 473 AN: 60394

GnomAD4 genome AF: 0.00517 AC: 788 AN: 152300 Hom.: 6 Cov.: 32 AF XY: 0.00500 AC XY: 372 AN XY: 74468

African (AFR) AF: 0.00142 AC: 59 AN: 41574

American (AMR) AF: 0.00576 AC: 88 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0205 AC: 71 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4832

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10616

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00750 AC: 510 AN: 68024

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00746 Hom.: 12

Bravo AF: 0.00528

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00674 AC: 58

ExAC AF: 0.00566 AC: 687

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00943

EpiControl AF: 0.00812

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Autosomal recessive distal renal tubular acidosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.59	T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.22
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.58
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.026	D
Polyphen		0.60	P
Vest4		0.31
MVP		0.75
MPC		0.34
ClinPred		0.016	T
GERP RS		-2.4
Varity_R		0.071
gMVP		0.42
Mutation Taster		=98/2	polymorphism

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: rs150777839; hg19: chr7-138406746; COSMIC: COSV59476036;