NM_001085429.2:c.68C>G

Variant names:

• chr7-138798172-C-G
• rs767692106
• NM_001085429.2:c.68C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001085429.2(TMEM213):​c.68C>G​(p.Ser23Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S23L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TMEM213 NM_001085429.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.478
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07421866).

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.68C>G	p.Ser23Trp	missense	Exon 1 of 3	NP_001078898.1	A2RRL7-1
	ATP6V0A4	NM_020632.3	MANE Select	c.-259G>C		5_prime_UTR	Exon 1 of 22	NP_065683.2	Q9HBG4
	ATP6V0A4	NM_130840.3		c.-156G>C		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.68C>G	p.Ser23Trp	missense	Exon 1 of 3	ENSP00000390407.2	A2RRL7-1
	TMEM213	ENST00000397602.7	TSL:1	c.68C>G	p.Ser23Trp	missense	Exon 1 of 3	ENSP00000380727.3	A2RRL7-3
	ATP6V0A4	ENST00000310018.7	TSL:1 MANE Select	c.-259G>C		5_prime_UTR	Exon 1 of 22	ENSP00000308122.2	Q9HBG4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442454 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 715458

African (AFR) AF: 0.00 AC: 0 AN: 33158

American (AMR) AF: 0.00 AC: 0 AN: 41290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25688

East Asian (EAS) AF: 0.00 AC: 0 AN: 38830

South Asian (SAS) AF: 0.00 AC: 0 AN: 82796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52076

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1103130

Other (OTH) AF: 0.00 AC: 0 AN: 59738

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.024	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.48
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.016
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.030	D
Polyphen		0.0020	B
Vest4		0.27
MutPred		0.24		Loss of disorder (P = 0)
MVP		0.030
MPC		1.1
ClinPred		0.86	D
GERP RS		-1.4
PromoterAI		-0.020	Neutral
Varity_R		0.051
gMVP		0.24
Mutation Taster		=100/0	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: rs767692106; hg19: chr7-138482917;