Genetic Variant TMEM132E:p.Pro35Gln (chr17-34626163-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001304438.2(TMEM132E):c.104C>A(p.Pro35Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. P35L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TMEM132E
NM_001304438.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.651

Publications

1 publications found

Variant links:

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]

TMEM132E Gene-Disease associations (from GenCC):

hearing loss, autosomal recessive 99
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen

TMEM132E links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.14627686).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001304438.2. 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
	TMEM132E	NM_001304438.2	MANE Select	c.104C>A	p.Pro35Gln	missense	Exon 2 of 9	NP_001291367.1	Q6IEE7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM132E	ENST00000631683.2	TSL:5 MANE Select	c.104C>A	p.Pro35Gln	missense	Exon 2 of 9	ENSP00000487800.2	Q6IEE7
	TMEM132E	ENST00000321639.7	TSL:5	c.104C>A	p.Pro35Gln	missense	Exon 2 of 10	ENSP00000316532.5	A0A494BWY4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1399260

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

690208

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31848

American (AMR)

AF:

0.00

AC:

AN:

36456

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23976

East Asian (EAS)

AF:

0.00

AC:

AN:

37214

South Asian (SAS)

AF:

0.00

AC:

AN:

77564

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4078

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1082300

Other (OTH)

AF:

0.00

AC:

AN:

57662

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.0021

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.75

M_CAP

Benign

0.0074

MetaRNN

Benign

0.15

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

PhyloP100

0.65

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.32

REVEL

Benign

0.15

Sift

Benign

0.042

Sift4G

Benign

0.24

Polyphen

0.96

Vest4

0.27

MutPred

0.17

Loss of glycosylation at P35 (P = 0.0032)

MVP

0.072

MPC

0.44

ClinPred

0.33

GERP RS

5.1

Varity_R

0.11

gMVP

0.30

Mutation Taster

=89/11

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over