Genetic Variant TLE3:p.Met353Ile (chr15-70058151-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005078.4(TLE3):c.1059G>A(p.Met353Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,666 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TLE3
NM_005078.4 missense, splice_region

Scores

Splicing: ADA: 0.002578

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.502

Variant links:

Genes affected

TLE3 (HGNC:11839): (TLE family member 3, transcriptional corepressor) This gene encodes a transcriptional co-repressor protein that belongs to the transducin-like enhancer family of proteins. The members of this family function in the Notch signaling pathway that regulates determination of cell fate during development. Expression of this gene has been associated with a favorable outcome to chemotherapy with taxanes for ovarian carcinoma. Alternate splicing results in multiple transcript variants. Additional alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known. [provided by RefSeq, Sep 2013]

TLE3 links:

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ACMG classification

Classification made for transcript

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=0.11599499).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLE3	NM_001105192.3 link	c.1051+8G>A		splice_region_variant, intron_variant	Intron 12 of 19	ENST00000451782.7	NP_001098662.1	Q04726-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLE3	ENST00000451782.7 link	c.1051+8G>A		splice_region_variant, intron_variant	Intron 12 of 19	5	NM_001105192.3	ENSP00000394717.3		Q04726-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000803

AC:

AN:

249124

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135148

show subpopulations

Gnomad AFR exome

AF:

0.0000646

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:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461666

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1059G>A (p.M353I) alteration is located in exon 12 (coding exon 12) of the TLE3 gene. This alteration results from a G to A substitution at nucleotide position 1059, causing the methionine (M) at amino acid position 353 to be replaced by an isoleucine (I). 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

0.20

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.16

T;T;T;T;.;T;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.79

T;T;T;T;T;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.12

T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;.;.;.;.;.;N

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.31

N;.;N;N;N;N;N

Sift

Benign

0.47

T;.;T;T;T;T;T

Sift4G

Benign

0.41

T;T;T;T;T;T;T

Polyphen

0.0020

B;.;.;.;B;.;.

Vest4

0.43

MutPred

0.44

Loss of glycosylation at S355 (P = 0.1164);Loss of glycosylation at S355 (P = 0.1164);.;.;.;.;Loss of glycosylation at S355 (P = 0.1164);

MVP

0.10

MPC

0.53

ClinPred

0.089

GERP RS

3.6

Varity_R

0.089

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0026

dbscSNV1_RF

Benign

0.094

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