3-113788729-A-C

Position:

• chr3-113788729-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_001690.4(ATP6V1A):​c.733A>C​(p.Thr245Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ATP6V1A NM_001690.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.70

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATP6V1A. . Gene score misZ 3.3731 (greater than the threshold 3.09). Trascript score misZ 4.7152 (greater than threshold 3.09). GenCC has associacion of gene with autosomal recessive cutis laxa type 2, classic type, undetermined early-onset epileptic encephalopathy, epileptic encephalopathy, infantile or early childhood, 3, autosomal recessive cutis laxa type 2D.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V1A	NM_001690.4	c.733A>C	p.Thr245Pro	missense_variant	7/15	ENST00000273398.8	NP_001681.2
ATP6V1A	XM_047448305.1	c.733A>C	p.Thr245Pro	missense_variant	7/15		XP_047304261.1
ATP6V1A	XM_047448306.1	c.733A>C	p.Thr245Pro	missense_variant	8/16		XP_047304262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V1A	ENST00000273398.8	c.733A>C	p.Thr245Pro	missense_variant	7/15	1	NM_001690.4	ENSP00000273398.3
ATP6V1A	ENST00000703904.2	c.733A>C	p.Thr245Pro	missense_variant	8/16			ENSP00000515542.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74354

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

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

Oct 08, 2021

The c.733A>C (p.T245P) alteration is located in exon 7 (coding exon 6) of the ATP6V1A gene. This alteration results from an A to C substitution at nucleotide position 733, causing the threonine (T) at amino acid position 245 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of <0.01% (1/31386) total alleles studied. The highest observed frequency was 0.12% (1/848) of Latino alleles. This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. 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	0.95
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Pathogenic	3.9	H
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.66
MutPred		0.68		Loss of catalytic residue at T245 (P = 0.0055);
MVP		0.93
MPC		2.0
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.93
gMVP		0.99

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: rs1383329082; hg19: chr3-113507576;