chr7-138771243-A-G

Variant names:

• chr7-138771243-A-G
• rs10258719
• NM_020632.3:c.5T>C

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.5T>C​(p.Val2Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.718 in 1,612,452 control chromosomes in the GnomAD database, including 417,944 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.72 (39285 hom., cov: 31)
  • Exomes 𝑓: 0.72 (378659 hom.)
• Consequence: ATP6V0A4 NM_020632.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.12
• Publications: 44 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=7.507831E-7).
• BP6: Variant 7-138771243-A-G is Benign according to our data. Variant chr7-138771243-A-G is described in ClinVar as Benign. ClinVar VariationId is 261345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.749 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V0A4	NM_020632.3	MANE Select	c.5T>C	p.Val2Ala	missense	Exon 3 of 22	NP_065683.2
	ATP6V0A4	NM_130840.3		c.5T>C	p.Val2Ala	missense	Exon 2 of 21	NP_570855.2
	ATP6V0A4	NM_130841.3		c.5T>C	p.Val2Ala	missense	Exon 2 of 21	NP_570856.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V0A4	ENST00000310018.7	TSL:1 MANE Select	c.5T>C	p.Val2Ala	missense	Exon 3 of 22	ENSP00000308122.2
	ATP6V0A4	ENST00000353492.4	TSL:1	c.5T>C	p.Val2Ala	missense	Exon 2 of 21	ENSP00000253856.6
	ATP6V0A4	ENST00000393054.5	TSL:5	c.5T>C	p.Val2Ala	missense	Exon 2 of 21	ENSP00000376774.1

Frequencies

GnomAD3 genomes AF: 0.716 AC: 108749 AN: 151864 Hom.: 39244 Cov.: 31

Gnomad AFR AF: 0.744

Gnomad AMI AF: 0.773

Gnomad AMR AF: 0.617

Gnomad ASJ AF: 0.766

Gnomad EAS AF: 0.513

Gnomad SAS AF: 0.770

Gnomad FIN AF: 0.749

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.724

Gnomad OTH AF: 0.721

GnomAD2 exomes AF: 0.693 AC: 174239 AN: 251418 AF XY: 0.703

Gnomad AFR exome AF: 0.743

Gnomad AMR exome AF: 0.532

Gnomad ASJ exome AF: 0.757

Gnomad EAS exome AF: 0.483

Gnomad FIN exome AF: 0.753

Gnomad NFE exome AF: 0.728

Gnomad OTH exome AF: 0.715

GnomAD4 exome AF: 0.718 AC: 1048445 AN: 1460470 Hom.: 378659 Cov.: 47 AF XY: 0.720 AC XY: 523470 AN XY: 726670

African (AFR) AF: 0.749 AC: 25034 AN: 33430

American (AMR) AF: 0.540 AC: 24151 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.759 AC: 19840 AN: 26130

East Asian (EAS) AF: 0.513 AC: 20352 AN: 39674

South Asian (SAS) AF: 0.774 AC: 66722 AN: 86226

European-Finnish (FIN) AF: 0.752 AC: 40122 AN: 53376

Middle Eastern (MID) AF: 0.740 AC: 4263 AN: 5762

European-Non Finnish (NFE) AF: 0.725 AC: 804807 AN: 1110804

Other (OTH) AF: 0.715 AC: 43154 AN: 60348

GnomAD4 genome AF: 0.716 AC: 108840 AN: 151982 Hom.: 39285 Cov.: 31 AF XY: 0.715 AC XY: 53096 AN XY: 74288

African (AFR) AF: 0.745 AC: 30875 AN: 41448

American (AMR) AF: 0.616 AC: 9403 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.766 AC: 2660 AN: 3472

East Asian (EAS) AF: 0.513 AC: 2637 AN: 5144

South Asian (SAS) AF: 0.769 AC: 3697 AN: 4806

European-Finnish (FIN) AF: 0.749 AC: 7913 AN: 10560

Middle Eastern (MID) AF: 0.772 AC: 227 AN: 294

European-Non Finnish (NFE) AF: 0.724 AC: 49199 AN: 67976

Other (OTH) AF: 0.722 AC: 1524 AN: 2112

Alfa AF: 0.719 Hom.: 133337

Bravo AF: 0.702

TwinsUK AF: 0.708 AC: 2627

ALSPAC AF: 0.718 AC: 2768

ESP6500AA AF: 0.746 AC: 3287

ESP6500EA AF: 0.725 AC: 6236

ExAC AF: 0.704 AC: 85464

Asia WGS AF: 0.652 AC: 2265 AN: 3478

EpiCase AF: 0.730

EpiControl AF: 0.724

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Autosomal recessive distal renal tubular acidosis (2)
-	-	1	Bailey-Bloch congenital myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.041
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.88
DEOGEN2	Benign	0.057	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	7.5e-7	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.6	N
PhyloP100		1.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	2.4	N
REVEL	Benign	0.21
Sift	Benign	0.12	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.011
MPC		0.23
ClinPred		0.0039	T
GERP RS		1.9
Varity_R		0.029
gMVP		0.18
Mutation Taster		=58/42	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: rs10258719; hg19: chr7-138455988; COSMIC: COSV59476423;