rs61747674

Variant names:

• chr7-138749314-G-T
• rs61747674
• NM_020632.3:c.1033C>A

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.1033C>A​(p.Leu345Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00753 in 1,549,738 control chromosomes in the GnomAD database, including 46 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0077 (44 hom.)
• Consequence: ATP6V0A4 NM_020632.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.42
• Publications: 11 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=0.01126197).
• BP6: Variant 7-138749314-G-T is Benign according to our data. Variant chr7-138749314-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261340.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 = 0.00593 (840/141600) while in subpopulation NFE AF = 0.0088 (571/64892). AF 95% confidence interval is 0.0082. There are 2 homozygotes in GnomAd4. There are 402 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V0A4	NM_020632.3	MANE Select	c.1033C>A	p.Leu345Ile	missense	Exon 12 of 22	NP_065683.2
	ATP6V0A4	NM_130840.3		c.1033C>A	p.Leu345Ile	missense	Exon 11 of 21	NP_570855.2
	ATP6V0A4	NM_130841.3		c.1033C>A	p.Leu345Ile	missense	Exon 11 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.1033C>A	p.Leu345Ile	missense	Exon 12 of 22	ENSP00000308122.2
	ATP6V0A4	ENST00000353492.4	TSL:1	c.1033C>A	p.Leu345Ile	missense	Exon 11 of 21	ENSP00000253856.6
	ATP6V0A4	ENST00000393054.5	TSL:5	c.1033C>A	p.Leu345Ile	missense	Exon 11 of 21	ENSP00000376774.1

Frequencies

GnomAD3 genomes AF: 0.00594 AC: 840 AN: 141480 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00840

Gnomad ASJ AF: 0.000887

Gnomad EAS AF: 0.000202

Gnomad SAS AF: 0.000472

Gnomad FIN AF: 0.00227

Gnomad MID AF: 0.00658

Gnomad NFE AF: 0.00878

Gnomad OTH AF: 0.00866

GnomAD2 exomes AF: 0.00466 AC: 1132 AN: 242760 AF XY: 0.00455

Gnomad AFR exome AF: 0.00208

Gnomad AMR exome AF: 0.00604

Gnomad ASJ exome AF: 0.00122

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00212

Gnomad NFE exome AF: 0.00696

Gnomad OTH exome AF: 0.00660

GnomAD4 exome AF: 0.00769 AC: 10832 AN: 1408138 Hom.: 44 Cov.: 36 AF XY: 0.00744 AC XY: 5227 AN XY: 702280

African (AFR) AF: 0.00238 AC: 76 AN: 31982

American (AMR) AF: 0.00641 AC: 280 AN: 43662

Ashkenazi Jewish (ASJ) AF: 0.00153 AC: 38 AN: 24782

East Asian (EAS) AF: 0.00 AC: 0 AN: 37446

South Asian (SAS) AF: 0.00123 AC: 105 AN: 85308

European-Finnish (FIN) AF: 0.00198 AC: 96 AN: 48590

Middle Eastern (MID) AF: 0.00235 AC: 13 AN: 5526

European-Non Finnish (NFE) AF: 0.00911 AC: 9781 AN: 1073262

Other (OTH) AF: 0.00769 AC: 443 AN: 57580

GnomAD4 genome AF: 0.00593 AC: 840 AN: 141600 Hom.: 2 Cov.: 31 AF XY: 0.00586 AC XY: 402 AN XY: 68618

African (AFR) AF: 0.00288 AC: 110 AN: 38214

American (AMR) AF: 0.00831 AC: 113 AN: 13592

Ashkenazi Jewish (ASJ) AF: 0.000887 AC: 3 AN: 3384

East Asian (EAS) AF: 0.000202 AC: 1 AN: 4946

South Asian (SAS) AF: 0.000472 AC: 2 AN: 4234

European-Finnish (FIN) AF: 0.00227 AC: 21 AN: 9232

Middle Eastern (MID) AF: 0.00704 AC: 2 AN: 284

European-Non Finnish (NFE) AF: 0.00880 AC: 571 AN: 64892

Other (OTH) AF: 0.00857 AC: 17 AN: 1984

Alfa AF: 0.00637 Hom.: 14

Bravo AF: 0.00534

TwinsUK AF: 0.0116 AC: 43

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00698 AC: 60

ExAC AF: 0.00408 AC: 495

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.4
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.28
Sift	Benign	0.11	T
Sift4G	Benign	0.14	T
Polyphen		0.87	P
Vest4		0.24
MVP		0.77
MPC		0.47
ClinPred		0.015	T
GERP RS		2.7
Varity_R		0.071
gMVP		0.33
Mutation Taster		=100/0	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: rs61747674; hg19: chr7-138434059; COSMIC: COSV100023908; COSMIC: COSV100023908;