7-138734165-G-C

Variant names:

• chr7-138734165-G-C
• rs1026435
• NM_020632.3:c.1662C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020632.3(ATP6V0A4):​c.1662C>G​(p.Phe554Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F554F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATP6V0A4 NM_020632.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.143
• Publications: 25 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834

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.1662C>G	p.Phe554Leu	missense	Exon 16 of 22	NP_065683.2
	ATP6V0A4	NM_130840.3		c.1662C>G	p.Phe554Leu	missense	Exon 15 of 21	NP_570855.2
	ATP6V0A4	NM_130841.3		c.1662C>G	p.Phe554Leu	missense	Exon 15 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.1662C>G	p.Phe554Leu	missense	Exon 16 of 22	ENSP00000308122.2
	ATP6V0A4	ENST00000353492.4	TSL:1	c.1662C>G	p.Phe554Leu	missense	Exon 15 of 21	ENSP00000253856.6
	ATP6V0A4	ENST00000393054.5	TSL:5	c.1662C>G	p.Phe554Leu	missense	Exon 15 of 21	ENSP00000376774.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 55

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	11
DANN	Benign	0.94
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.26	N
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.14
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.68		Loss of helix (P = 0.2022)
MVP		0.43
MPC		0.83
ClinPred		0.86	D
GERP RS		-11
Varity_R		0.46
gMVP		0.63
Mutation Taster		=50/50

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: rs1026435; hg19: chr7-138418910;