Variant 5-171309468-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000296921.6(TLX3):c.103C>A(p.Pro35Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,443,584 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: not found (cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

TLX3
ENST00000296921.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.79

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:

ENSG00000275038 (HGNC:):

ENSG00000275038 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15871584).

BS2

High AC in GnomAdExome4 at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLX3	NM_021025.4 linkuse as main transcript	c.103C>A	p.Pro35Thr	missense_variant	1/3	ENST00000296921.6	NP_066305.2	O43711

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLX3	ENST00000296921.6 linkuse as main transcript	c.103C>A	p.Pro35Thr	missense_variant	1/3	1	NM_021025.4	ENSP00000296921.5		O43711
ENSG00000275038	ENST00000619056.2 linkuse as main transcript	n.244+66G>T		intron_variant		6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000480

AC:

AN:

208260

Hom.:

AF XY:

0.0000260

AC XY:

AN XY:

115386

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000535

Gnomad NFE exome

AF:

0.000101

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000229

AC:

AN:

1443584

Hom.:

Cov.:

AF XY:

0.0000195

AC XY:

AN XY:

717340

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000394

Gnomad4 NFE exome

AF:

0.0000263

Gnomad4 OTH exome

AF:

0.0000336

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000680

AC:

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

May 13, 2024

The c.103C>A (p.P35T) alteration is located in exon 1 (coding exon 1) of the TLX3 gene. This alteration results from a C to A substitution at nucleotide position 103, causing the proline (P) at amino acid position 35 to be replaced by a threonine (T). 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

0.064

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.19

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.054

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.38

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.31

MutationAssessor

Benign

1.1

MutationTaster

Benign

0.77

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.37

REVEL

Benign

0.19

Sift

Benign

0.40

Sift4G

Benign

0.45

Polyphen

0.0

Vest4

0.30

MutPred

0.22

Gain of phosphorylation at P35 (P = 0.0037);

MVP

0.86

MPC

0.34

ClinPred

0.060

GERP RS

4.4

Varity_R

0.14

gMVP

0.44

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