17-34626143-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001304438.2(TMEM132E):c.84C>G(p.His28Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000889 in 1,529,394 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. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000091 (0 hom.)
• Consequence: TMEM132E NM_001304438.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.36

Genes affected

TMEM132E (HGNC:26991): (transmembrane protein 132E) Involved in posterior lateral line neuromast hair cell development. Predicted to be located in cell body. Implicated in autosomal recessive nonsyndromic deafness 99. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.036391824).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM132E	NM_001304438.2	c.84C>G	p.His28Gln	missense_variant	2/9	ENST00000631683.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM132E	ENST00000631683.2	c.84C>G	p.His28Gln	missense_variant	2/9	5	NM_001304438.2	P1
TMEM132E	ENST00000321639.7	c.84C>G	p.His28Gln	missense_variant	2/10	5

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000121 AC: 17 AN: 140356 Hom.: 0 AF XY: 0.000160 AC XY: 12 AN XY: 75082

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 SAS exome AF: 0.000186

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000915 AC: 126 AN: 1377170 Hom.: 0 Cov.: 31 AF XY: 0.0000900 AC XY: 61 AN XY: 677558

Gnomad4 AFR exome AF: 0.0000643

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000550

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000110

Gnomad4 OTH exome AF: 0.0000353

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000198 Hom.: 0

Bravo AF: 0.000132

ExAC AF: 0.0000822 AC: 9

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Apr 24, 2023	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 595779). This variant has not been reported in the literature in individuals affected with TMEM132E-related conditions. This variant is present in population databases (rs774704736, gnomAD 0.02%). This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 28 of the TMEM132E protein (p.His28Gln). -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 30, 2018	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 26, 2024

The c.84C>G (p.H28Q) alteration is located in exon 2 (coding exon 2) of the TMEM132E gene. This alteration results from a C to G substitution at nucleotide position 84, causing the histidine (H) at amino acid position 28 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	16
Dann	Benign	0.92
DEOGEN2	Benign	0.0039	T;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.65	T;T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.036	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.70	N;.
REVEL	Benign	0.071
Sift	Benign	0.20	T;.
Sift4G	Benign	0.51	T;T
Polyphen		0.0090	B;.
Vest4		0.14
MutPred		0.091		Loss of methylation at R26 (P = 0.0432);Loss of methylation at R26 (P = 0.0432);
MVP		0.095
MPC		0.47
ClinPred		0.034	T
GERP RS		2.9
Varity_R		0.067
gMVP		0.12

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: rs774704736; hg19: chr17-32953162;