NM_020632.3:c.1675A>T

Variant names:

• chr7-138734152-T-A
• rs369486474
• NM_020632.3:c.1675A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020632.3(ATP6V0A4):​c.1675A>T​(p.Ser559Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATP6V0A4 NM_020632.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 2.28
• Publications: 0 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6V0A4	NM_020632.3	c.1675A>T	p.Ser559Cys	missense_variant	Exon 16 of 22	ENST00000310018.7	NP_065683.2
ATP6V0A4	NM_130840.3	c.1675A>T	p.Ser559Cys	missense_variant	Exon 15 of 21		NP_570855.2
ATP6V0A4	NM_130841.3	c.1675A>T	p.Ser559Cys	missense_variant	Exon 15 of 21		NP_570856.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6V0A4	ENST00000310018.7	c.1675A>T	p.Ser559Cys	missense_variant	Exon 16 of 22	1	NM_020632.3	ENSP00000308122.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460544 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726702

African (AFR) AF: 0.0000299 AC: 1 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110852

Other (OTH) AF: 0.00 AC: 0 AN: 60336

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Renal tubular acidosis, distal, 3, with or without sensorineural hearing loss Uncertain:1

Feb 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;D;D;.;.;D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	.;D;.;D;D;.
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D
MetaSVM	Pathogenic	0.79	D
MutationAssessor	Pathogenic	3.5	M;M;M;.;.;M
PhyloP100		2.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.2	D;D;.;.;.;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0020	D;D;.;.;.;D
Sift4G	Uncertain	0.0040	D;D;.;.;.;D
Polyphen		1.0	D;D;D;.;.;D
Vest4		0.74
MutPred		0.77		Loss of catalytic residue at S559 (P = 0.1797);Loss of catalytic residue at S559 (P = 0.1797);Loss of catalytic residue at S559 (P = 0.1797);.;.;Loss of catalytic residue at S559 (P = 0.1797);
MVP		0.94
MPC		0.72
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.42
gMVP		0.68
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: rs369486474; hg19: chr7-138418897;