rs73166921

Variant names:

• chr7-138706809-G-A
• rs73166921
• NM_020632.3:c.2430-92C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-138706809-G-A
• chr7-138706809-G-C
• chr7-138706809-G-T

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.2430-92C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 1,565,506 control chromosomes in the GnomAD database, including 31,922 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3680 hom., cov: 29)
  • Exomes 𝑓: 0.20 (28242 hom.)
• Consequence: ATP6V0A4 NM_020632.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.63
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 7-138706809-G-A is Benign according to our data. Variant chr7-138706809-G-A is described in ClinVar as Benign. ClinVar VariationId is 1252452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.267 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.2430-92C>T		intron	N/A	NP_065683.2	Q9HBG4
	ATP6V0A4	NM_130840.3		c.2430-92C>T		intron	N/A	NP_570855.2	Q9HBG4
	ATP6V0A4	NM_130841.3		c.2430-92C>T		intron	N/A	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.2430-92C>T		intron	N/A	ENSP00000308122.2	Q9HBG4
	ATP6V0A4	ENST00000353492.4	TSL:1	c.2430-92C>T		intron	N/A	ENSP00000253856.6	Q9HBG4
	ATP6V0A4	ENST00000393054.5	TSL:5	c.2430-92C>T		intron	N/A	ENSP00000376774.1	Q9HBG4

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32223 AN: 150820 Hom.: 3673 Cov.: 29

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.0476

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.341

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.242

GnomAD4 exome AF: 0.196 AC: 277614 AN: 1414570 Hom.: 28242 Cov.: 31 AF XY: 0.198 AC XY: 139149 AN XY: 702234

African (AFR) AF: 0.283 AC: 9241 AN: 32640

American (AMR) AF: 0.129 AC: 5200 AN: 40336

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 6913 AN: 25186

East Asian (EAS) AF: 0.0622 AC: 2348 AN: 37724

South Asian (SAS) AF: 0.220 AC: 18360 AN: 83436

European-Finnish (FIN) AF: 0.176 AC: 6889 AN: 39106

Middle Eastern (MID) AF: 0.285 AC: 1612 AN: 5654

European-Non Finnish (NFE) AF: 0.197 AC: 215291 AN: 1091816

Other (OTH) AF: 0.200 AC: 11760 AN: 58672

GnomAD4 genome AF: 0.214 AC: 32238 AN: 150936 Hom.: 3680 Cov.: 29 AF XY: 0.212 AC XY: 15618 AN XY: 73616

African (AFR) AF: 0.271 AC: 11113 AN: 40978

American (AMR) AF: 0.192 AC: 2881 AN: 15002

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 965 AN: 3466

East Asian (EAS) AF: 0.0475 AC: 244 AN: 5134

South Asian (SAS) AF: 0.211 AC: 1012 AN: 4794

European-Finnish (FIN) AF: 0.187 AC: 1943 AN: 10394

Middle Eastern (MID) AF: 0.353 AC: 103 AN: 292

European-Non Finnish (NFE) AF: 0.197 AC: 13355 AN: 67896

Other (OTH) AF: 0.239 AC: 496 AN: 2072

Alfa AF: 0.198 Hom.: 473

Bravo AF: 0.217

Asia WGS AF: 0.139 AC: 484 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.0050
DANN	Benign	0.61
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs73166921; hg19: chr7-138391554;