Variant 9-81611838-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_005077.5(TLE1):c.1185C>A(p.His395Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000375 in 1,561,616 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00039 ( 0 hom. )

Consequence

TLE1
NM_005077.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.52

Variant links:

Genes affected

TLE1 (HGNC:11837): (TLE family member 1, transcriptional corepressor) Enables identical protein binding activity and transcription corepressor activity. Involved in negative regulation of I-kappaB kinase/NF-kappaB signaling; negative regulation of anoikis; and regulation of gene expression. Located in cytosol and nucleoplasm. Part of beta-catenin-TCF complex. [provided by Alliance of Genome Resources, Apr 2022]

TLE1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLE1	NM_005077.5 linkuse as main transcript	c.1185C>A	p.His395Gln	missense_variant	13/20	ENST00000376499.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
TLE1	ENST00000376499.8 linkuse as main transcript	c.1185C>A	p.His395Gln	missense_variant	13/20	1	NM_005077.5	P1
TLE1	ENST00000491534.5 linkuse as main transcript	c.546C>A	p.His182Gln	missense_variant	5/5	5
TLE1	ENST00000376484.2 linkuse as main transcript	c.267C>A	p.His89Gln	missense_variant	2/4	3
TLE1	ENST00000464999.1 linkuse as main transcript			downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152272

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000964

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000367

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000155

AC:

AN:

200378

Hom.:

AF XY:

0.000136

AC XY:

AN XY:

110416

show subpopulations

Gnomad AFR exome

AF:

0.000167

Gnomad AMR exome

AF:

0.0000425

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000481

Gnomad NFE exome

AF:

0.000285

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000393

AC:

554

AN:

1409344

Hom.:

Cov.:

AF XY:

0.000415

AC XY:

291

AN XY:

700496

show subpopulations

Gnomad4 AFR exome

AF:

0.0000685

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:

0.0000569

Gnomad4 NFE exome

AF:

0.000470

Gnomad4 OTH exome

AF:

0.000636

GnomAD4 genome

AF:

0.000204

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.0000964

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000367

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000254

Hom.:

Bravo

AF:

0.000234

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000198

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2023

The c.1185C>A (p.H395Q) alteration is located in exon 13 (coding exon 13) of the TLE1 gene. This alteration results from a C to A substitution at nucleotide position 1185, causing the histidine (H) at amino acid position 395 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

0.25

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.24

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.72

D;T

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.080

MetaRNN

Uncertain

0.74

D;D

MetaSVM

Benign

-0.34

MutationAssessor

Uncertain

2.7

M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-5.0

D;D

REVEL

Benign

0.27

Sift

Benign

0.036

D;D

Sift4G

Uncertain

0.055

T;D

Polyphen

0.96

P;.

Vest4

0.84

MutPred

0.40

Loss of catalytic residue at N396 (P = 0.1119);.;

MVP

0.57

MPC

0.48

ClinPred

0.36

GERP RS

5.0

Varity_R

0.50

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

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