7-138734165-G-T

Position:

• chr7-138734165-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020632.3(ATP6V0A4):​c.1662C>A​(p.Phe554Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. F554F) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ATP6V0A4 NM_020632.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.143

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6V0A4	NM_020632.3	c.1662C>A	p.Phe554Leu	missense_variant	16/22	ENST00000310018.7
ATP6V0A4	NM_130840.3	c.1662C>A	p.Phe554Leu	missense_variant	15/21
ATP6V0A4	NM_130841.3	c.1662C>A	p.Phe554Leu	missense_variant	15/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6V0A4	ENST00000310018.7	c.1662C>A	p.Phe554Leu	missense_variant	16/22	1	NM_020632.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461158 Hom.: 0 Cov.: 55 AF XY: 0.00000275 AC XY: 2 AN XY: 726904

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;D;D;.;.;D
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.22	N
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.1	M;M;M;.;.;M
MutationTaster	Benign	0.00029	P;P;P
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.5	D;D;.;.;.;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.014	D;D;.;.;.;D
Sift4G	Uncertain	0.031	D;D;.;.;.;D
Polyphen		1.0	D;D;D;.;.;D
Vest4		0.85
MutPred		0.68		Loss of helix (P = 0.2022);Loss of helix (P = 0.2022);Loss of helix (P = 0.2022);.;.;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1026435; hg19: chr7-138418910;