rs150052634

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_005077.5(TLE1):​c.1936C>T​(p.Arg646Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000693 in 1,613,320 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00074 ( 1 hom. )

Consequence

TLE1
NM_005077.5 missense

Scores

9
6
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.30

Publications

1 publications found
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 Gene-Disease associations (from GenCC):
  • movement disorder
    Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.815

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TLE1NM_005077.5 linkc.1936C>T p.Arg646Cys missense_variant Exon 17 of 20 ENST00000376499.8 NP_005068.2 Q04724Q59EF7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TLE1ENST00000376499.8 linkc.1936C>T p.Arg646Cys missense_variant Exon 17 of 20 1 NM_005077.5 ENSP00000365682.3 Q04724
ENSG00000301585ENST00000779997.1 linkn.59G>A non_coding_transcript_exon_variant Exon 1 of 2

Frequencies

GnomAD3 genomes
AF:
0.000283
AC:
43
AN:
152104
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.000485
Gnomad OTH
AF:
0.000480
GnomAD2 exomes
AF:
0.000259
AC:
65
AN:
250818
AF XY:
0.000288
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.0000580
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000494
Gnomad OTH exome
AF:
0.000491
GnomAD4 exome
AF:
0.000736
AC:
1075
AN:
1461216
Hom.:
1
Cov.:
32
AF XY:
0.000671
AC XY:
488
AN XY:
726876
show subpopulations
African (AFR)
AF:
0.000149
AC:
5
AN:
33460
American (AMR)
AF:
0.0000672
AC:
3
AN:
44668
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26104
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39656
South Asian (SAS)
AF:
0.0000696
AC:
6
AN:
86188
European-Finnish (FIN)
AF:
0.0000187
AC:
1
AN:
53398
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5762
European-Non Finnish (NFE)
AF:
0.000905
AC:
1006
AN:
1111604
Other (OTH)
AF:
0.000894
AC:
54
AN:
60376
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.462
Heterozygous variant carriers
0
62
124
187
249
311
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
44
88
132
176
220
<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
AF:
0.000283
AC:
43
AN:
152104
Hom.:
0
Cov.:
32
AF XY:
0.000215
AC XY:
16
AN XY:
74312
show subpopulations
African (AFR)
AF:
0.000169
AC:
7
AN:
41424
American (AMR)
AF:
0.000131
AC:
2
AN:
15272
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5184
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10604
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.000485
AC:
33
AN:
68010
Other (OTH)
AF:
0.000480
AC:
1
AN:
2082
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.498
Heterozygous variant carriers
0
3
6
8
11
14
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000457
Hom.:
0
Bravo
AF:
0.000321
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.000198
AC:
24
EpiCase
AF:
0.000764
EpiControl
AF:
0.000297

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 08, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1936C>T (p.R646C) alteration is located in exon 17 (coding exon 17) of the TLE1 gene. This alteration results from a C to T substitution at nucleotide position 1936, causing the arginine (R) at amino acid position 646 to be replaced by a cysteine (C). 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
Pathogenic
0.96
BayesDel_addAF
Benign
-0.047
T
BayesDel_noAF
Uncertain
0.030
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.83
D
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Pathogenic
1.0
D
M_CAP
Benign
0.042
D
MetaRNN
Pathogenic
0.82
D
MetaSVM
Benign
-0.91
T
MutationAssessor
Uncertain
2.9
M
PhyloP100
2.3
PrimateAI
Pathogenic
0.94
D
PROVEAN
Pathogenic
-7.4
D
REVEL
Uncertain
0.31
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.81
MVP
0.57
MPC
2.5
ClinPred
0.96
D
GERP RS
4.8
Varity_R
0.88
gMVP
0.55
Mutation Taster
=36/64
disease causing

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

Other links and lift over

dbSNP: rs150052634; hg19: chr9-84202637; API