17-34581134-C-T

Position:

• chr17-34581134-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001304438.2(TMEM132E):​c.58C>T​(p.Leu20Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000287 in 1,521,218 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: TMEM132E NM_001304438.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.555

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07426828).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM132E	NM_001304438.2	c.58C>T	p.Leu20Phe	missense_variant	1/9	ENST00000631683.2	NP_001291367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM132E	ENST00000631683.2	c.58C>T	p.Leu20Phe	missense_variant	1/9	5	NM_001304438.2	ENSP00000487800.2
TMEM132E	ENST00000321639.7	c.58C>T	p.Leu20Phe	missense_variant	1/10	5		ENSP00000316532.5

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152146 Hom.: 0 Cov.: 34

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: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000168 AC: 20 AN: 119070 Hom.: 0 AF XY: 0.000243 AC XY: 16 AN XY: 65756

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: 0.00

Gnomad FIN exome AF: 0.000405

Gnomad NFE exome AF: 0.000356

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000283 AC: 388 AN: 1369072 Hom.: 1 Cov.: 34 AF XY: 0.000323 AC XY: 218 AN XY: 675874

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000291

Gnomad4 NFE exome AF: 0.000345

Gnomad4 OTH exome AF: 0.000122

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152146 Hom.: 0 Cov.: 34 AF XY: 0.000296 AC XY: 22 AN XY: 74324

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: 0.000282

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.000955

Alfa AF: 0.000643 Hom.: 0

Bravo AF: 0.000215

ExAC AF: 0.000172 AC: 18

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 29, 2023

The c.58C>T (p.L20F) alteration is located in exon 1 (coding exon 1) of the TMEM132E gene. This alteration results from a C to T substitution at nucleotide position 58, causing the leucine (L) at amino acid position 20 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 11, 2024

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 20 of the TMEM132E protein (p.Leu20Phe). This variant is present in population databases (rs774898682, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with TMEM132E-related conditions. ClinVar contains an entry for this variant (Variation ID: 1414121). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Not Available". The phenylalanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0022	T;T
Eigen	Benign	-0.083
Eigen_PC	Benign	-0.022
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.56	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.074	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.75	N;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.49	N;.
REVEL	Benign	0.093
Sift	Uncertain	0.013	D;.
Sift4G	Uncertain	0.055	T;T
Polyphen		0.99	D;.
Vest4		0.094
MVP		0.30
MPC		0.51
ClinPred		0.18	T
GERP RS		3.4
Varity_R		0.13
gMVP		0.30

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: rs774898682; hg19: chr17-32908153;