2-74515204-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016170.5(TLX2):​c.398C>T​(p.Thr133Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,540,194 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T133S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

TLX2
NM_016170.5 missense, splice_region

Scores

2
14
3
Splicing: ADA: 0.9992
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.25
Variant links:
Genes affected
TLX2 (HGNC:5057): (T cell leukemia homeobox 2) This gene is a member of an orphan homeobox-containing transcription factor family. Studies of the mouse ortholog have shown that the encoded protein is crucial for the development of the enteric nervous system; in humans, loss-of-function may play a role in tumorigenesis of gastrointestinal stromal tumors. [provided by RefSeq, May 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TLX2NM_016170.5 linkc.398C>T p.Thr133Met missense_variant, splice_region_variant Exon 1 of 3 ENST00000233638.8 NP_057254.1 O43763

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TLX2ENST00000233638.8 linkc.398C>T p.Thr133Met missense_variant, splice_region_variant Exon 1 of 3 1 NM_016170.5 ENSP00000233638.6 O43763
TLX2ENST00000621092.1 linkc.12-429C>T intron_variant Intron 2 of 3 1 ENSP00000482690.1 F1T0F2
TLX2ENST00000497238.1 linkn.704C>T splice_region_variant, non_coding_transcript_exon_variant Exon 3 of 4 5

Frequencies

GnomAD3 genomes
AF:
0.000125
AC:
19
AN:
152220
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.000250
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000122
AC:
17
AN:
138974
Hom.:
0
AF XY:
0.0000791
AC XY:
6
AN XY:
75860
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000122
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:
0.000258
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000179
AC:
249
AN:
1387974
Hom.:
0
Cov.:
34
AF XY:
0.000163
AC XY:
112
AN XY:
685340
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000139
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:
0.000216
Gnomad4 OTH exome
AF:
0.000190
GnomAD4 genome
AF:
0.000125
AC:
19
AN:
152220
Hom.:
0
Cov.:
33
AF XY:
0.000121
AC XY:
9
AN XY:
74374
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000250
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000172
Hom.:
0
Bravo
AF:
0.000102
ExAC
AF:
0.0000299
AC:
3

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 07, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.398C>T (p.T133M) alteration is located in exon 1 (coding exon 1) of the TLX2 gene. This alteration results from a C to T substitution at nucleotide position 398, causing the threonine (T) at amino acid position 133 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
0.25
BayesDel_addAF
Benign
-0.054
T
BayesDel_noAF
Uncertain
-0.010
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.78
D
Eigen
Uncertain
0.39
Eigen_PC
Uncertain
0.30
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Pathogenic
0.30
D
MetaRNN
Uncertain
0.47
T
MetaSVM
Uncertain
0.57
D
MutationAssessor
Uncertain
2.5
M
PrimateAI
Uncertain
0.74
T
PROVEAN
Uncertain
-3.4
D
REVEL
Uncertain
0.53
Sift
Uncertain
0.0070
D
Sift4G
Uncertain
0.051
T
Polyphen
1.0
D
Vest4
0.13
MVP
0.92
MPC
2.2
ClinPred
0.78
D
GERP RS
4.2
Varity_R
0.28
gMVP
0.61

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.87
SpliceAI score (max)
0.050
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: rs375415258; hg19: chr2-74742331; COSMIC: COSV99029123; COSMIC: COSV99029123; API