Variant 10-101131975-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_005521.4(TLX1):c.434C>T(p.Ala145Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000888 in 1,508,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

TLX1
NM_005521.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.33

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020496666).

BS2

High AC in GnomAd4 at 65 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLX1	NM_005521.4 linkuse as main transcript	c.434C>T	p.Ala145Val	missense_variant	1/3	ENST00000370196.11	NP_005512.1	P31314-1
TLX1	NM_001195517.2 linkuse as main transcript	c.434C>T	p.Ala145Val	missense_variant	1/3		NP_001182446.1	P31314-2
TLX1	XM_011539744.4 linkuse as main transcript	c.434C>T	p.Ala145Val	missense_variant	1/3		XP_011538046.1
TLX1NB	NR_130724.1 linkuse as main transcript	n.580-4877G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TLX1	ENST00000370196.11 linkuse as main transcript	c.434C>T	p.Ala145Val	missense_variant	1/3	1	NM_005521.4	ENSP00000359215.6	P31314-1
TLX1	ENST00000467928.2 linkuse as main transcript	c.434C>T	p.Ala145Val	missense_variant	1/3	1		ENSP00000434914.2	P31314-2
TLX1	ENST00000463716.3 linkuse as main transcript	c.248C>T	p.Ala83Val	missense_variant	1/2	3		ENSP00000434358.3	G3V1B7

Frequencies

GnomAD3 genomes

AF:

0.000427

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00154

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000736

AC:

AN:

163006

Hom.:

AF XY:

0.0000323

AC XY:

AN XY:

92826

show subpopulations

Gnomad AFR exome

AF:

0.00132

Gnomad AMR exome

AF:

0.0000442

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000509

AC:

AN:

1356652

Hom.:

Cov.:

AF XY:

0.0000431

AC XY:

AN XY:

672224

show subpopulations

Gnomad4 AFR exome

AF:

0.00192

Gnomad4 AMR exome

AF:

0.000122

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000133

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000187

Gnomad4 OTH exome

AF:

0.000107

GnomAD4 genome

AF:

0.000427

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.00154

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:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000342

Hom.:

Bravo

AF:

0.000555

ESP6500AA

AF:

0.00141

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000135

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

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 28, 2022

The c.434C>T (p.A145V) alteration is located in exon 1 (coding exon 1) of the TLX1 gene. This alteration results from a C to T substitution at nucleotide position 434, causing the alanine (A) at amino acid position 145 to be replaced by a valine (V). 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

-0.32

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;.;.

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.74

T;T;T

M_CAP

Pathogenic

0.70

MetaRNN

Benign

0.020

T;T;T

MetaSVM

Benign

-0.29

MutationAssessor

Benign

1.1

L;L;.

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.30

N;N;.

REVEL

Benign

0.20

Sift

Benign

0.030

D;T;.

Sift4G

Benign

0.33

T;T;T

Polyphen

0.36

B;.;.

Vest4

0.12

MVP

0.95

ClinPred

0.035

GERP RS

4.2

Varity_R

0.14

gMVP

0.19

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