chr7-138706385-C-T

Variant names:

• chr7-138706385-C-T
• rs8846
• NM_020632.3:c.*239G>A

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.*239G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 529,434 control chromosomes in the GnomAD database, including 11,700 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4041 hom., cov: 31)
  • Exomes 𝑓: 0.19 (7659 hom.)
• Consequence: ATP6V0A4 NM_020632.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.659
• Publications: 7 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=-0.75).
• BP6: Variant 7-138706385-C-T is Benign according to our data. Variant chr7-138706385-C-T is described in ClinVar as Benign. ClinVar VariationId is 358999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.295 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.*239G>A		3_prime_UTR	Exon 22 of 22	NP_065683.2	Q9HBG4
	ATP6V0A4	NM_130840.3		c.*239G>A		3_prime_UTR	Exon 21 of 21	NP_570855.2	Q9HBG4
	ATP6V0A4	NM_130841.3		c.*239G>A		3_prime_UTR	Exon 21 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.*239G>A		3_prime_UTR	Exon 22 of 22	ENSP00000308122.2	Q9HBG4
	ATP6V0A4	ENST00000393054.5	TSL:5	c.*239G>A		3_prime_UTR	Exon 21 of 21	ENSP00000376774.1	Q9HBG4
	ATP6V0A4	ENST00000645515.1		c.*239G>A		3_prime_UTR	Exon 22 of 22	ENSP00000496421.1	Q9HBG4

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33765 AN: 151998 Hom.: 4035 Cov.: 31

Gnomad AFR AF: 0.299

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.0484

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.242

GnomAD4 exome AF: 0.193 AC: 72706 AN: 377318 Hom.: 7659 Cov.: 3 AF XY: 0.195 AC XY: 38713 AN XY: 198736

African (AFR) AF: 0.305 AC: 3335 AN: 10918

American (AMR) AF: 0.152 AC: 2549 AN: 16734

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 3078 AN: 11426

East Asian (EAS) AF: 0.0607 AC: 1508 AN: 24862

South Asian (SAS) AF: 0.219 AC: 9433 AN: 43010

European-Finnish (FIN) AF: 0.172 AC: 3856 AN: 22474

Middle Eastern (MID) AF: 0.289 AC: 452 AN: 1562

European-Non Finnish (NFE) AF: 0.196 AC: 44115 AN: 224652

Other (OTH) AF: 0.202 AC: 4380 AN: 21680

GnomAD4 genome AF: 0.222 AC: 33776 AN: 152116 Hom.: 4041 Cov.: 31 AF XY: 0.221 AC XY: 16425 AN XY: 74372

African (AFR) AF: 0.299 AC: 12402 AN: 41488

American (AMR) AF: 0.197 AC: 3009 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 968 AN: 3472

East Asian (EAS) AF: 0.0484 AC: 251 AN: 5190

South Asian (SAS) AF: 0.215 AC: 1036 AN: 4828

European-Finnish (FIN) AF: 0.188 AC: 1988 AN: 10578

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.197 AC: 13388 AN: 67980

Other (OTH) AF: 0.240 AC: 505 AN: 2106

Alfa AF: 0.207 Hom.: 2076

Bravo AF: 0.225

Asia WGS AF: 0.141 AC: 493 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.6
DANN	Benign	0.75
PhyloP100		-0.66
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: rs8846; hg19: chr7-138391130;