7-138798112-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001085429.2(TMEM213):c.8G>A(p.Arg3His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,598,030 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0099 (15 hom., cov: 30)
  • Exomes 𝑓: 0.0012 (30 hom.)
• Consequence: TMEM213 NM_001085429.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -5.26

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00197649).
• BP6: Variant 7-138798112-G-A is Benign according to our data. Variant chr7-138798112-G-A is described in ClinVar as [Benign]. Clinvar id is 909588.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00992 (1510/152182) while in subpopulation AFR AF= 0.0338 (1403/41500). AF 95% confidence interval is 0.0323. There are 15 homozygotes in gnomad4. There are 707 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM213	NM_001085429.2	c.8G>A	p.Arg3His	missense_variant	1/3	ENST00000442682.7
ATP6V0A4	NM_020632.3	c.-199C>T		5_prime_UTR_variant	1/22	ENST00000310018.7
ATP6V0A4	NM_130840.3	c.-96C>T		5_prime_UTR_variant	1/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM213	ENST00000442682.7	c.8G>A	p.Arg3His	missense_variant	1/3	1	NM_001085429.2	P4
ATP6V0A4	ENST00000310018.7	c.-199C>T		5_prime_UTR_variant	1/22	1	NM_020632.3	P1

Frequencies

GnomAD3 genomes AF: 0.00988 AC: 1503 AN: 152064 Hom.: 14 Cov.: 30

Gnomad AFR AF: 0.0337

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00259 AC: 571 AN: 220852 Hom.: 8 AF XY: 0.00216 AC XY: 259 AN XY: 119668

Gnomad AFR exome AF: 0.0325

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.00253

Gnomad EAS exome AF: 0.0000617

Gnomad SAS exome AF: 0.000147

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000292

Gnomad OTH exome AF: 0.00200

GnomAD4 exome AF: 0.00124 AC: 1800 AN: 1445848 Hom.: 30 Cov.: 31 AF XY: 0.00110 AC XY: 788 AN XY: 717614

Gnomad4 AFR exome AF: 0.0351

Gnomad4 AMR exome AF: 0.00285

Gnomad4 ASJ exome AF: 0.00218

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.0000961

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.000234

Gnomad4 OTH exome AF: 0.00306

GnomAD4 genome AF: 0.00992 AC: 1510 AN: 152182 Hom.: 15 Cov.: 30 AF XY: 0.00950 AC XY: 707 AN XY: 74412

Gnomad4 AFR AF: 0.0338

Gnomad4 AMR AF: 0.00477

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00232 Hom.: 8

Bravo AF: 0.0118

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0289 AC: 126

ESP6500EA AF: 0.000468 AC: 4

ExAC AF: 0.00277 AC: 335

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive distal renal tubular acidosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.0040
Dann	Benign	0.90
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.51	T;T;T;T
MetaRNN	Benign	0.0020	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.29	N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.28	N;N;N;N
REVEL	Benign	0.010
Sift	Benign	0.34	T;T;T;T
Sift4G	Benign	0.32	T;T;T;T
Polyphen		0.0	B;B;.;.
Vest4		0.071
MVP		0.014
MPC		0.36
ClinPred		0.0082	T
GERP RS		-9.0
Varity_R		0.019
gMVP		0.24

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: rs138299222; hg19: chr7-138482857; COSMIC: COSV99047555; COSMIC: COSV99047555;