3-113781071-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001690.4(ATP6V1A):c.104C>T(p.Ala35Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000827 in 1,450,530 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A35A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: ATP6V1A NM_001690.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.36

Genes affected

ATP6V1A (HGNC:851): (ATPase H+ transporting V1 subunit A) 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 encoded protein is one of two V1 domain A subunit isoforms and is found in all tissues. Transcript variants derived from alternative polyadenylation exist. [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
• PP2: Missense variant where missense usually causes diseases, ATP6V1A

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6V1A	NM_001690.4	c.104C>T	p.Ala35Val	missense_variant	3/15	ENST00000273398.8
ATP6V1A	XM_047448305.1	c.104C>T	p.Ala35Val	missense_variant	3/15
ATP6V1A	XM_047448306.1	c.104C>T	p.Ala35Val	missense_variant	4/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6V1A	ENST00000273398.8	c.104C>T	p.Ala35Val	missense_variant	3/15	1	NM_001690.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000417 AC: 1 AN: 239936 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 129850

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000926

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000827 AC: 12 AN: 1450530 Hom.: 0 Cov.: 30 AF XY: 0.00000693 AC XY: 5 AN XY: 721328

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: 0.00000994

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 29, 2023

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 35 of the ATP6V1A protein (p.Ala35Val). This variant has not been reported in the literature in individuals affected with ATP6V1A-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATP6V1A protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.38	T;T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.077	D
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Uncertain	-0.060	T
MutationAssessor	Benign	1.7	L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.27	T;T;T
Polyphen		0.49	P;.;.
Vest4		0.52
MVP		0.36
MPC		0.95
ClinPred		0.84	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.28
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs367827756; hg19: chr3-113499918; COSMIC: COSV56365231; COSMIC: COSV56365231;