Genetic Variant TLE4:p.Ala289Pro (chr9-79706828-G-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_007005.6(TLE4):c.865G>C(p.Ala289Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000499 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

TLE4
NM_007005.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.62

Variant links:

Genes affected

TLE4 (HGNC:11840): (TLE family member 4, transcriptional corepressor) Predicted to enable transcription corepressor activity. Predicted to be involved in negative regulation of canonical Wnt signaling pathway. Predicted to act upstream of or within Wnt signaling pathway; cellular response to leukemia inhibitory factor; and negative regulation of transcription by RNA polymerase II. Located in nucleoplasm. Part of beta-catenin-TCF complex. [provided by Alliance of Genome Resources, Apr 2022]

TLE4 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17749226).

BS2

High AC in GnomAdExome4 at 73 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLE4	NM_007005.6 link	c.865G>C	p.Ala289Pro	missense_variant	Exon 11 of 20	ENST00000376552.8	NP_008936.2	Q04727-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLE4	ENST00000376552.8 link	c.865G>C	p.Ala289Pro	missense_variant	Exon 11 of 20	1	NM_007005.6	ENSP00000365735.2		Q04727-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000321

AC:

AN:

249568

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135400

show subpopulations

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:

0.00

Gnomad NFE exome

AF:

0.0000706

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000499

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000605

AC XY:

AN XY:

727242

show subpopulations

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:

0.00

Gnomad4 NFE exome

AF:

0.0000647

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000378

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000331

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.865G>C (p.A289P) alteration is located in exon 11 (coding exon 11) of the TLE4 gene. This alteration results from a G to C substitution at nucleotide position 865, causing the alanine (A) at amino acid position 289 to be replaced by a proline (P). 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

0.095

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;.;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

0.49

N;N;.

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.74

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.13

T;T;T

Sift4G

Benign

0.29

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.25

MVP

0.10

MPC

0.45

ClinPred

0.13

GERP RS

5.9

Varity_R

0.23

gMVP

0.29

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

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