19-3053974-C-T

Variant summary

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

The NM_001130.6(TLE5):​c.439G>A​(p.Val147Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,610,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 34)
Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

TLE5
NM_001130.6 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.31
Variant links:
Genes affected
TLE5 (HGNC:307): (TLE family member 5, transcriptional modulator) The protein encoded by this gene is similar in sequence to the amino terminus of Drosophila enhancer of split groucho, a protein involved in neurogenesis during embryonic development. The encoded protein, which belongs to the groucho/TLE family of proteins, can function as a homooligomer or as a heteroologimer with other family members to dominantly repress the expression of other family member genes. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

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=0.10236135).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TLE5NM_001130.6 linkc.439G>A p.Val147Met missense_variant 7/7 ENST00000327141.9 NP_001121.2 Q08117-1Q8WY48
TLE5NM_198969.1 linkc.640G>A p.Val214Met missense_variant 7/7 NP_945320.1 Q08117-2Q8WY48
TLE5NM_198970.2 linkc.436G>A p.Val146Met missense_variant 7/7 NP_945321.1 Q08117Q8WY48
TLE5XM_006722664.2 linkc.637G>A p.Val213Met missense_variant 7/7 XP_006722727.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TLE5ENST00000327141.9 linkc.439G>A p.Val147Met missense_variant 7/71 NM_001130.6 ENSP00000317537.4 Q08117-1

Frequencies

GnomAD3 genomes
AF:
0.0000789
AC:
12
AN:
152148
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000132
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000719
AC:
17
AN:
236284
Hom.:
0
AF XY:
0.0000769
AC XY:
10
AN XY:
130120
show subpopulations
Gnomad AFR exome
AF:
0.0000713
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:
0.000154
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000155
AC:
226
AN:
1458028
Hom.:
0
Cov.:
41
AF XY:
0.000142
AC XY:
103
AN XY:
725206
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000225
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000197
Gnomad4 OTH exome
AF:
0.0000665
GnomAD4 genome
AF:
0.0000789
AC:
12
AN:
152148
Hom.:
0
Cov.:
34
AF XY:
0.0000807
AC XY:
6
AN XY:
74316
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000678
Hom.:
0
Bravo
AF:
0.0000567
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000118
AC:
1
ExAC
AF:
0.0000836
AC:
10

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 submitterclinical testingAmbry GeneticsOct 25, 2023The c.640G>A (p.V214M) alteration is located in exon 7 (coding exon 7) of the AES gene. This alteration results from a G to A substitution at nucleotide position 640, causing the valine (V) at amino acid position 214 to be replaced by a methionine (M). 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
0.082
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
19
DANN
Benign
0.96
DEOGEN2
Benign
0.15
.;T;.
Eigen
Benign
-0.22
Eigen_PC
Benign
-0.22
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Uncertain
0.86
D;D;D
M_CAP
Benign
0.034
D
MetaRNN
Benign
0.10
T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
1.0
.;L;.
PrimateAI
Uncertain
0.75
T
PROVEAN
Benign
-0.010
N;N;.
REVEL
Benign
0.021
Sift
Benign
0.056
T;T;.
Sift4G
Benign
0.14
T;T;T
Polyphen
0.031
.;B;.
Vest4
0.12
MVP
0.38
MPC
0.37
ClinPred
0.046
T
GERP RS
3.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.076
gMVP
0.53

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.

Other links and lift over

dbSNP: rs375697013; hg19: chr19-3053972; COSMIC: COSV55592192; COSMIC: COSV55592192; API