rs3807154

Variant names:

• chr7-138732973-A-G
• rs3807154
• NM_020632.3:c.1812T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020632.3(ATP6V0A4):​c.1812T>C​(p.His604His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.71 in 1,613,270 control chromosomes in the GnomAD database, including 410,382 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (34209 hom., cov: 30)
  • Exomes 𝑓: 0.72 (376173 hom.)
• Consequence: ATP6V0A4 NM_020632.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0700
• Publications: 33 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=-0.9).
• BP6: Variant 7-138732973-A-G is Benign according to our data. Variant chr7-138732973-A-G is described in ClinVar as Benign. ClinVar VariationId is 261343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.791 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.1812T>C	p.His604His	synonymous	Exon 17 of 22	NP_065683.2
	ATP6V0A4	NM_130840.3		c.1812T>C	p.His604His	synonymous	Exon 16 of 21	NP_570855.2
	ATP6V0A4	NM_130841.3		c.1812T>C	p.His604His	synonymous	Exon 16 of 21	NP_570856.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V0A4	ENST00000310018.7	TSL:1 MANE Select	c.1812T>C	p.His604His	synonymous	Exon 17 of 22	ENSP00000308122.2
	ATP6V0A4	ENST00000353492.4	TSL:1	c.1812T>C	p.His604His	synonymous	Exon 16 of 21	ENSP00000253856.6
	ATP6V0A4	ENST00000393054.5	TSL:5	c.1812T>C	p.His604His	synonymous	Exon 16 of 21	ENSP00000376774.1

Frequencies

GnomAD3 genomes AF: 0.660 AC: 100206 AN: 151724 Hom.: 34202 Cov.: 30

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.799

Gnomad AMR AF: 0.759

Gnomad ASJ AF: 0.690

Gnomad EAS AF: 0.812

Gnomad SAS AF: 0.738

Gnomad FIN AF: 0.768

Gnomad MID AF: 0.703

Gnomad NFE AF: 0.717

Gnomad OTH AF: 0.655

GnomAD2 exomes AF: 0.729 AC: 183187 AN: 251388 AF XY: 0.730

Gnomad AFR exome AF: 0.457

Gnomad AMR exome AF: 0.830

Gnomad ASJ exome AF: 0.696

Gnomad EAS exome AF: 0.822

Gnomad FIN exome AF: 0.763

Gnomad NFE exome AF: 0.716

Gnomad OTH exome AF: 0.730

GnomAD4 exome AF: 0.715 AC: 1045437 AN: 1461428 Hom.: 376173 Cov.: 60 AF XY: 0.717 AC XY: 521051 AN XY: 727064

African (AFR) AF: 0.465 AC: 15564 AN: 33466

American (AMR) AF: 0.822 AC: 36758 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.691 AC: 18064 AN: 26134

East Asian (EAS) AF: 0.795 AC: 31571 AN: 39698

South Asian (SAS) AF: 0.734 AC: 63296 AN: 86256

European-Finnish (FIN) AF: 0.763 AC: 40737 AN: 53420

Middle Eastern (MID) AF: 0.702 AC: 4049 AN: 5768

European-Non Finnish (NFE) AF: 0.713 AC: 792602 AN: 1111592

Other (OTH) AF: 0.709 AC: 42796 AN: 60374

GnomAD4 genome AF: 0.660 AC: 100240 AN: 151842 Hom.: 34209 Cov.: 30 AF XY: 0.665 AC XY: 49374 AN XY: 74212

African (AFR) AF: 0.470 AC: 19453 AN: 41370

American (AMR) AF: 0.759 AC: 11566 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.690 AC: 2396 AN: 3470

East Asian (EAS) AF: 0.812 AC: 4193 AN: 5166

South Asian (SAS) AF: 0.739 AC: 3544 AN: 4798

European-Finnish (FIN) AF: 0.768 AC: 8098 AN: 10550

Middle Eastern (MID) AF: 0.714 AC: 210 AN: 294

European-Non Finnish (NFE) AF: 0.717 AC: 48683 AN: 67940

Other (OTH) AF: 0.651 AC: 1370 AN: 2104

Alfa AF: 0.698 Hom.: 68966

Bravo AF: 0.653

Asia WGS AF: 0.731 AC: 2541 AN: 3478

EpiCase AF: 0.719

EpiControl AF: 0.727

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Autosomal recessive distal renal tubular acidosis (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.093
DANN	Benign	0.36
PhyloP100		-0.070
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: rs3807154; hg19: chr7-138417718; COSMIC: COSV108112176; COSMIC: COSV108112176;