Genetic Variant TLE1:p.Asn494Asn (chr9-81593124-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_005077.5(TLE1):c.1482C>T(p.Asn494Asn) variant causes a synonymous change. The variant allele was found at a frequency of 0.00482 in 1,614,148 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0037 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0049 ( 25 hom. )

Consequence

TLE1
NM_005077.5 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 6.92

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 was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 9-81593124-G-A is Benign according to our data. Variant chr9-81593124-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2659272.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLE1	NM_005077.5 link	c.1482C>T	p.Asn494Asn	synonymous_variant	Exon 15 of 20	ENST00000376499.8	NP_005068.2	Q04724Q59EF7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLE1	ENST00000376499.8 link	c.1482C>T	p.Asn494Asn	synonymous_variant	Exon 15 of 20	1	NM_005077.5	ENSP00000365682.3		Q04724

Frequencies

GnomAD3 genomes

AF:

0.00372

AC:

566

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00445

Gnomad ASJ

AF:

0.00980

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00339

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00538

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00404

AC:

1016

AN:

251470

AF XY:

0.00403

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00356

Gnomad ASJ exome

AF:

0.00744

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00333

Gnomad NFE exome

AF:

0.00570

Gnomad OTH exome

AF:

0.00538

GnomAD4 exome

AF:

0.00494

AC:

7216

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00488

AC XY:

3550

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

33480

American (AMR)

AF:

0.00378

AC:

169

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00895

AC:

234

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00152

AC:

131

AN:

86258

European-Finnish (FIN)

AF:

0.00339

AC:

181

AN:

53418

Middle Eastern (MID)

AF:

0.00624

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00550

AC:

6118

AN:

1112012

Other (OTH)

AF:

0.00546

AC:

330

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

504

1009

1513

2018

2522

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00372

AC:

566

AN:

152256

Hom.:

Cov.:

AF XY:

0.00360

AC XY:

268

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00103

AC:

AN:

41554

American (AMR)

AF:

0.00445

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00980

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00339

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00538

AC:

366

AN:

68018

Other (OTH)

AF:

0.00521

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

120

150

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00506

Hom.:

Bravo

AF:

0.00377

EpiCase

AF:

0.00660

EpiControl

AF:

0.00717

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TLE1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

8.4

(source)

DANN

Benign

0.78

PhyloP100

6.9

Mutation Taster

=56/44

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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9-81593124-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over