17-42478484-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001130021.3(ATP6V0A1):c.528C>A(p.Asn176Lys) 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 benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATP6V0A1 NM_001130021.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.58

Genes affected

ATP6V0A1 (HGNC:865): (ATPase H+ transporting V0 subunit a1) This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle 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. Additional isoforms of many of the V1 and V0 subunit proteins are encoded by multiple genes or alternatively spliced transcript variants. This gene encodes one of three A subunit proteins and the encoded protein is associated with clathrin-coated vesicles. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ATP6V0A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.26842517).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6V0A1	NM_001130021.3	c.528C>A	p.Asn176Lys	missense_variant	7/22	ENST00000343619.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6V0A1	ENST00000343619.9	c.528C>A	p.Asn176Lys	missense_variant	7/22	1	NM_001130021.3	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2023

The c.549C>A (p.N183K) alteration is located in exon 7 (coding exon 6) of the ATP6V0A1 gene. This alteration results from a C to A substitution at nucleotide position 549, causing the asparagine (N) at amino acid position 183 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Benign	-0.077
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.3	L;.;.;.;L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.49	N;N;N;.;N;.;.
REVEL	Uncertain	0.39
Sift	Benign	0.61	T;T;T;.;T;.;.
Sift4G	Benign	0.89	T;T;T;T;T;T;T
Polyphen		0.0080	B;B;.;B;B;.;.
Vest4		0.47
MutPred		0.52		Gain of methylation at N176 (P = 0.021);.;.;.;Gain of methylation at N176 (P = 0.021);.;.;
MVP		0.17
MPC		1.2
ClinPred		0.39	T
GERP RS		6.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.41
gMVP		0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs770195864; hg19: chr17-40630502;