rs368646400

Variant names:

• chr7-138798050-G-A
• rs368646400
• NM_020632.3:c.-137C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020632.3(ATP6V0A4):​c.-137C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 1,559,220 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (9 hom., cov: 30)
  • Exomes 𝑓: 0.0027 (120 hom.)
• Consequence: ATP6V0A4 NM_020632.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.924
• 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]

TMEM213 (HGNC:27220): (transmembrane protein 213) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 7-138798050-G-A is Benign according to our data. Variant chr7-138798050-G-A is described in ClinVar as Benign. ClinVar VariationId is 359036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00148 (225/152142) while in subpopulation SAS AF = 0.0457 (220/4818). AF 95% confidence interval is 0.0407. There are 9 homozygotes in GnomAd4. There are 169 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020632.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V0A4	NM_020632.3	MANE Select	c.-137C>T		5_prime_UTR	Exon 1 of 22	NP_065683.2	Q9HBG4
	TMEM213	NM_001085429.2	MANE Select	c.-55G>A		5_prime_UTR	Exon 1 of 3	NP_001078898.1	A2RRL7-1
	ATP6V0A4	NM_130840.3		c.-34C>T		5_prime_UTR	Exon 1 of 21	NP_570855.2	Q9HBG4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V0A4	ENST00000310018.7	TSL:1 MANE Select	c.-137C>T		5_prime_UTR	Exon 1 of 22	ENSP00000308122.2	Q9HBG4
	TMEM213	ENST00000442682.7	TSL:1 MANE Select	c.-55G>A		5_prime_UTR	Exon 1 of 3	ENSP00000390407.2	A2RRL7-1
	ATP6V0A4	ENST00000353492.4	TSL:1	c.-34C>T		5_prime_UTR	Exon 1 of 21	ENSP00000253856.6	Q9HBG4

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 225 AN: 152024 Hom.: 9 Cov.: 30

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0456

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00642 AC: 1059 AN: 165004 AF XY: 0.00878

Gnomad AFR exome AF: 0.000351

Gnomad AMR exome AF: 0.0000395

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000149

Gnomad OTH exome AF: 0.00109

GnomAD4 exome AF: 0.00266 AC: 3739 AN: 1407078 Hom.: 120 Cov.: 31 AF XY: 0.00394 AC XY: 2738 AN XY: 694832

African (AFR) AF: 0.000156 AC: 5 AN: 31986

American (AMR) AF: 0.0000276 AC: 1 AN: 36254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25240

East Asian (EAS) AF: 0.00 AC: 0 AN: 36408

South Asian (SAS) AF: 0.0446 AC: 3554 AN: 79686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49714

Middle Eastern (MID) AF: 0.00123 AC: 7 AN: 5708

European-Non Finnish (NFE) AF: 0.0000111 AC: 12 AN: 1083720

Other (OTH) AF: 0.00274 AC: 160 AN: 58362

GnomAD4 genome AF: 0.00148 AC: 225 AN: 152142 Hom.: 9 Cov.: 30 AF XY: 0.00227 AC XY: 169 AN XY: 74372

African (AFR) AF: 0.0000482 AC: 2 AN: 41508

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.0457 AC: 220 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67986

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000330 Hom.: 0

Bravo AF: 0.000238

Asia WGS AF: 0.0180 AC: 61 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal recessive distal renal tubular acidosis (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.4
DANN	Benign	0.57
PhyloP100		-0.92
PromoterAI		0.023	Neutral
Mutation Taster		=297/3	polymorphism

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: rs368646400; hg19: chr7-138482795;