chr7-138709632-TC-CT

Variant names:

• chr7-138709632-TC-CT
• NM_020632.3:c.2420_2421delGAinsAG
• ATP6V0A4 p.Arg807Gln

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS1_Very_Strong

The NM_020632.3(ATP6V0A4):​c.2420_2421delGAinsAG​(p.Arg807Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATP6V0A4 NM_020632.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.13
• Publications: 0 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: Likely_pathogenic. The variant received 8 ACMG points.

• PS1: Transcript NM_020632.3 (ATP6V0A4) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

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.2420_2421delGAinsAG	p.Arg807Gln	missense	N/A	NP_065683.2	Q9HBG4
	ATP6V0A4	NM_130840.3		c.2420_2421delGAinsAG	p.Arg807Gln	missense	N/A	NP_570855.2	Q9HBG4
	ATP6V0A4	NM_130841.3		c.2420_2421delGAinsAG	p.Arg807Gln	missense	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.2420_2421delGAinsAG	p.Arg807Gln	missense	N/A	ENSP00000308122.2	Q9HBG4
	ATP6V0A4	ENST00000353492.4	TSL:1	c.2420_2421delGAinsAG	p.Arg807Gln	missense	N/A	ENSP00000253856.6	Q9HBG4
	ATP6V0A4	ENST00000393054.5	TSL:5	c.2420_2421delGAinsAG	p.Arg807Gln	missense	N/A	ENSP00000376774.1	Q9HBG4

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr7-138394377;