chr7-138798112-G-A

Position:

chr7-138798112-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -5.26

Variant links:

Genes affected

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

TMEM213 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 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_multiple_submitters_no_conflicts, 2 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 GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TMEM213	NM_001085429.2 linkuse as main transcript	c.8G>A	p.Arg3His	missense_variant	1/3	ENST00000442682.7	NP_001078898.1
ATP6V0A4	NM_020632.3 linkuse as main transcript	c.-199C>T		5_prime_UTR_variant	1/22	ENST00000310018.7	NP_065683.2
ATP6V0A4	NM_130840.3 linkuse as main transcript	c.-96C>T		5_prime_UTR_variant	1/21		NP_570855.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM213	ENST00000442682.7 linkuse as main transcript	c.8G>A	p.Arg3His	missense_variant	1/3	1	NM_001085429.2	ENSP00000390407	P4	A2RRL7-1
ATP6V0A4	ENST00000310018.7 linkuse as main transcript	c.-199C>T		5_prime_UTR_variant	1/22	1	NM_020632.3	ENSP00000308122	P1

Frequencies

GnomAD3 genomes

AF:

0.00988

AC:

1503

AN:

152064

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00216

AC XY:

259

AN XY:

119668

show subpopulations

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.:

Cov.:

AF XY:

0.00110

AC XY:

788

AN XY:

717614

show subpopulations

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.:

Cov.:

AF XY:

0.00950

AC XY:

707

AN XY:

74412

show subpopulations

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.:

Bravo

AF:

0.0118

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0289

AC:

126

ESP6500EA

AF:

0.000468

AC:

ExAC

AF:

0.00277

AC:

335

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.0040

DANN

Benign

0.90

DEOGEN2

Benign

0.00090

.;T;.;.

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.51

T;T;T;T

MetaRNN

Benign

0.0020

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.29

N;N;N;N

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.24

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over