7-138706626-A-G

Position:

• chr7-138706626-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM4 PP5

The NM_020632.3(ATP6V0A4):​c.2521T>C​(p.Ter841Glnext*?) variant causes a stop lost change. The variant allele was found at a frequency of 0.000000684 in 1,461,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATP6V0A4 NM_020632.3 stop_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.88

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_020632.3 Downstream stopcodon found after 1 codons.
• PP5: Variant 7-138706626-A-G is Pathogenic according to our data. Variant chr7-138706626-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1331365.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V0A4	NM_020632.3	c.2521T>C	p.Ter841Glnext*?	stop_lost	22/22	ENST00000310018.7	NP_065683.2
ATP6V0A4	NM_130840.3	c.2521T>C	p.Ter841Glnext*?	stop_lost	21/21		NP_570855.2
ATP6V0A4	NM_130841.3	c.2521T>C	p.Ter841Glnext*?	stop_lost	21/21		NP_570856.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V0A4	ENST00000310018.7	c.2521T>C	p.Ter841Glnext*?	stop_lost	22/22	1	NM_020632.3	ENSP00000308122.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461700 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727164

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 01, 2024

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 06, 2021

Variant summary: ATP6V0A4 c.2521T>C (p.X841GlnextX53) changes the termination codon and is predicted to lead to an extended protein with additional amino acids added to the normal C-terminus. ATP6V0A4 c.2521T>C (p.X841GlnextX53) causes a frameshift which results in an extension of the protein. The variant was absent in 251264 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2521T>C has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Renal Tubular Acidosis, Distal, Autosomal Recessive (example, Stover_2002) and has been subsequently cited by others (example, Palazzo_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	0.0026	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Benign	0.89
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.83	D
Vest4		0.11
GERP RS		3.7

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-138391371;