10-101131807-G-A

Position:

chr10-101131807-G-A

Variant summary

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

The NM_005521.4(TLX1):c.266G>A(p.Gly89Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000525 in 1,389,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

TLX1
NM_005521.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.869

Variant links:

Genes affected

TLX1 (HGNC:5056): (T cell leukemia homeobox 1) This gene encodes a nuclear transcription factor that belongs to the NK-linked or NK-like (NKL) subfamily of homeobox genes. The encoded protein is required for normal development of the spleen during embryogenesis. This protein is also involved in specification of neuronal cell fates. Ectopic expression of this gene due to chromosomal translocations is associated with certain T-cell acute lymphoblastic leukemias. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2010]

TLX1 links:

TLX1NB (HGNC:):

TLX1NB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12978834).

BS2

High AC in GnomAd4 at 45 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLX1	NM_005521.4 linkuse as main transcript	c.266G>A	p.Gly89Asp	missense_variant	1/3	ENST00000370196.11	NP_005512.1	P31314-1
TLX1	NM_001195517.2 linkuse as main transcript	c.266G>A	p.Gly89Asp	missense_variant	1/3		NP_001182446.1	P31314-2
TLX1	XM_011539744.4 linkuse as main transcript	c.266G>A	p.Gly89Asp	missense_variant	1/3		XP_011538046.1
TLX1NB	NR_130724.1 linkuse as main transcript	n.580-4709C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TLX1	ENST00000370196.11 linkuse as main transcript	c.266G>A	p.Gly89Asp	missense_variant	1/3	1	NM_005521.4	ENSP00000359215.6	P31314-1
TLX1	ENST00000467928.2 linkuse as main transcript	c.266G>A	p.Gly89Asp	missense_variant	1/3	1		ENSP00000434914.2	P31314-2
TLX1	ENST00000463716.3 linkuse as main transcript	c.80G>A	p.Gly27Asp	missense_variant	1/2	3		ENSP00000434358.3	G3V1B7

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1237458

Hom.:

Cov.:

AF XY:

0.0000216

AC XY:

AN XY:

602366

show subpopulations

Gnomad4 AFR exome

AF:

0.000961

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:

0.00

Gnomad4 NFE exome

AF:

9.90e-7

Gnomad4 OTH exome

AF:

0.0000591

GnomAD4 genome

AF:

0.000296

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.00103

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000356

Hom.:

Bravo

AF:

0.000359

ExAC

AF:

0.0000578

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

Dec 02, 2024

The c.266G>A (p.G89D) alteration is located in exon 1 (coding exon 1) of the TLX1 gene. This alteration results from a G to A substitution at nucleotide position 266, causing the glycine (G) at amino acid position 89 to be replaced by an aspartic acid (D). 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

Uncertain

0.36

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;.;.

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.49

T;T;T

M_CAP

Pathogenic

0.94

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Uncertain

-0.057

MutationAssessor

Benign

2.0

M;M;.

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

0.18

N;N;.

REVEL

Benign

0.24

Sift

Benign

0.13

T;T;.

Sift4G

Benign

0.16

T;T;D

Polyphen

0.0040

B;.;.

Vest4

0.31

MutPred

0.30

Gain of solvent accessibility (P = 0.1014);Gain of solvent accessibility (P = 0.1014);.;

MVP

0.79

ClinPred

0.47

GERP RS

3.8

Varity_R

0.13

gMVP

0.58

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