7-138739555-C-T

Variant names:

• chr7-138739555-C-T
• rs74921348
• NM_020632.3:c.1557G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020632.3(ATP6V0A4):​c.1557G>A​(p.Pro519Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00709 in 1,614,096 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (65 hom.)
• Consequence: ATP6V0A4 NM_020632.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.39
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 7-138739555-C-T is Benign according to our data. Variant chr7-138739555-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 773499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.39 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00677 (1031/152266) while in subpopulation EAS AF = 0.0131 (68/5186). AF 95% confidence interval is 0.0106. There are 10 homozygotes in GnomAd4. There are 527 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 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.1557G>A	p.Pro519Pro	synonymous	Exon 15 of 22	NP_065683.2	Q9HBG4
	ATP6V0A4	NM_130840.3		c.1557G>A	p.Pro519Pro	synonymous	Exon 14 of 21	NP_570855.2	Q9HBG4
	ATP6V0A4	NM_130841.3		c.1557G>A	p.Pro519Pro	synonymous	Exon 14 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.1557G>A	p.Pro519Pro	synonymous	Exon 15 of 22	ENSP00000308122.2	Q9HBG4
	ATP6V0A4	ENST00000353492.4	TSL:1	c.1557G>A	p.Pro519Pro	synonymous	Exon 14 of 21	ENSP00000253856.6	Q9HBG4
	ATP6V0A4	ENST00000393054.5	TSL:5	c.1557G>A	p.Pro519Pro	synonymous	Exon 14 of 21	ENSP00000376774.1	Q9HBG4

Frequencies

GnomAD3 genomes AF: 0.00677 AC: 1030 AN: 152148 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00507

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0131

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0214

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00700

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00681 AC: 1711 AN: 251352 AF XY: 0.00674

Gnomad AFR exome AF: 0.00468

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0125

Gnomad FIN exome AF: 0.0204

Gnomad NFE exome AF: 0.00745

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00712 AC: 10415 AN: 1461830 Hom.: 65 Cov.: 31 AF XY: 0.00697 AC XY: 5070 AN XY: 727214

African (AFR) AF: 0.00505 AC: 169 AN: 33480

American (AMR) AF: 0.00215 AC: 96 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00768 AC: 305 AN: 39698

South Asian (SAS) AF: 0.000869 AC: 75 AN: 86258

European-Finnish (FIN) AF: 0.0198 AC: 1060 AN: 53408

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00750 AC: 8338 AN: 1111964

Other (OTH) AF: 0.00609 AC: 368 AN: 60394

GnomAD4 genome AF: 0.00677 AC: 1031 AN: 152266 Hom.: 10 Cov.: 32 AF XY: 0.00708 AC XY: 527 AN XY: 74434

African (AFR) AF: 0.00510 AC: 212 AN: 41558

American (AMR) AF: 0.00183 AC: 28 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0131 AC: 68 AN: 5186

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4822

European-Finnish (FIN) AF: 0.0214 AC: 227 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00700 AC: 476 AN: 68026

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00607 Hom.: 4

Bravo AF: 0.00546

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.00562

EpiControl AF: 0.00616

ClinVar

ClinVar submissions

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	4.5
DANN	Benign	0.68
PhyloP100		-1.4
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs74921348; hg19: chr7-138424300; COSMIC: COSV100023912;