chr7-138798161-C-T

Variant names:

• chr7-138798161-C-T
• rs373396667
• NM_001085429.2:c.57C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_001085429.2(TMEM213):​c.57C>T​(p.Ala19Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000288 in 1,598,628 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: TMEM213 NM_001085429.2 synonymous
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.426
• Publications: 0 publications found

Genes affected

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

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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP7: Synonymous conserved (PhyloP=0.426 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001085429.2. 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
	TMEM213	NM_001085429.2	MANE Select	c.57C>T	p.Ala19Ala	synonymous	Exon 1 of 3	NP_001078898.1	A2RRL7-1
	ATP6V0A4	NM_020632.3	MANE Select	c.-248G>A		5_prime_UTR	Exon 1 of 22	NP_065683.2	Q9HBG4
	ATP6V0A4	NM_130840.3		c.-145G>A		5_prime_UTR	Exon 1 of 21	NP_570855.2	Q9HBG4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM213	ENST00000442682.7	TSL:1 MANE Select	c.57C>T	p.Ala19Ala	synonymous	Exon 1 of 3	ENSP00000390407.2	A2RRL7-1
	TMEM213	ENST00000397602.7	TSL:1	c.57C>T	p.Ala19Ala	synonymous	Exon 1 of 3	ENSP00000380727.3	A2RRL7-3
	ATP6V0A4	ENST00000310018.7	TSL:1 MANE Select	c.-248G>A		5_prime_UTR	Exon 1 of 22	ENSP00000308122.2	Q9HBG4

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152162 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000287 AC: 63 AN: 219776 AF XY: 0.000270

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 FIN exome AF: 0.000159

Gnomad NFE exome AF: 0.000525

Gnomad OTH exome AF: 0.00146

GnomAD4 exome AF: 0.000296 AC: 428 AN: 1446350 Hom.: 0 Cov.: 31 AF XY: 0.000297 AC XY: 213 AN XY: 717788

African (AFR) AF: 0.00 AC: 0 AN: 33236

American (AMR) AF: 0.0000238 AC: 1 AN: 42082

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25748

East Asian (EAS) AF: 0.00 AC: 0 AN: 39044

South Asian (SAS) AF: 0.0000601 AC: 5 AN: 83182

European-Finnish (FIN) AF: 0.000172 AC: 9 AN: 52282

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.000353 AC: 390 AN: 1105110

Other (OTH) AF: 0.000367 AC: 22 AN: 59908

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152278 Hom.: 0 Cov.: 30 AF XY: 0.000175 AC XY: 13 AN XY: 74434

African (AFR) AF: 0.0000241 AC: 1 AN: 41552

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68028

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000196 Hom.: 0

Bravo AF: 0.000166

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	-0.70
CADD	Benign	7.1
DANN	Benign	0.61
PhyloP100		0.43
PromoterAI		-0.024	Neutral
Mutation Taster		=295/5	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: rs373396667; hg19: chr7-138482906;