Variant chr5-171311576-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_021025.4(TLX3):c.853C>T(p.Pro285Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000249 in 1,611,238 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00024 ( 1 hom. )

Consequence

TLX3
NM_021025.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.513

Variant links:

Genes affected

TLX3 (HGNC:13532): (T cell leukemia homeobox 3) The protein encoded by this gene is an orphan homeobox protein that encodes a DNA-binding nuclear transcription factor. A translocation [t(5;14)(q35;q32)] involving this gene is associated with T-cell acute lymphoblastic leukemia (T-ALL) in children and young adults. [provided by RefSeq, Nov 2015]

TLX3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0067889392).

BS2

High AC in GnomAd4 at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLX3	NM_021025.4 linkuse as main transcript	c.853C>T	p.Pro285Ser	missense_variant	3/3	ENST00000296921.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLX3	ENST00000296921.6 linkuse as main transcript	c.853C>T	p.Pro285Ser	missense_variant	3/3	1	NM_021025.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000423

AC:

104

AN:

245576

Hom.:

AF XY:

0.000413

AC XY:

AN XY:

133146

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00574

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000906

Gnomad FIN exome

AF:

0.0000474

Gnomad NFE exome

AF:

0.0000811

Gnomad OTH exome

AF:

0.00134

GnomAD4 exome

AF:

0.000241

AC:

351

AN:

1459054

Hom.:

Cov.:

AF XY:

0.000266

AC XY:

193

AN XY:

725670

show subpopulations

Gnomad4 AFR exome

AF:

0.0000898

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00637

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000864

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000639

Gnomad4 OTH exome

AF:

0.000547

GnomAD4 genome

AF:

0.000329

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.0104

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000469

Hom.:

Bravo

AF:

0.000291

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000346

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

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

Jul 21, 2021

The c.853C>T (p.P285S) alteration is located in exon 3 (coding exon 3) of the TLX3 gene. This alteration results from a C to T substitution at nucleotide position 853, causing the proline (P) at amino acid position 285 to be replaced by a serine (S). 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

0.10

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.15

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.55

M_CAP

Pathogenic

0.71

MetaRNN

Benign

0.0068

MetaSVM

Benign

-0.50

MutationAssessor

Benign

0.26

MutationTaster

Benign

0.83

PrimateAI

Uncertain

0.57

PROVEAN

Benign

0.030

REVEL

Benign

0.19

Sift

Benign

0.31

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.071

MVP

0.58

MPC

0.41

ClinPred

0.0081

GERP RS

3.3

Varity_R

0.060

gMVP

0.62

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