Genetic Variant TLX1:p.Leu47Ile (chr10-101131680-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005521.4(TLX1):c.139C>A(p.Leu47Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TLX1
NM_005521.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.808

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:37183): (TLX1 neighbor)

TLX1NB links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3534878).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLX1	NM_005521.4 link	c.139C>A	p.Leu47Ile	missense_variant	Exon 1 of 3	ENST00000370196.11	NP_005512.1	P31314-1
TLX1	NM_001195517.2 link	c.139C>A	p.Leu47Ile	missense_variant	Exon 1 of 3		NP_001182446.1	P31314-2
TLX1	XM_011539744.4 link	c.139C>A	p.Leu47Ile	missense_variant	Exon 1 of 3		XP_011538046.1
TLX1NB	NR_130724.1 link	n.580-4582G>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLX1	ENST00000370196.11 link	c.139C>A	p.Leu47Ile	missense_variant	Exon 1 of 3	1	NM_005521.4	ENSP00000359215.6		P31314-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1388170

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

689208

African (AFR)

AF:

0.00

AC:

AN:

27940

American (AMR)

AF:

0.00

AC:

AN:

33008

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22726

East Asian (EAS)

AF:

0.00

AC:

AN:

33320

South Asian (SAS)

AF:

0.00

AC:

AN:

76116

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5486

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1082108

Other (OTH)

AF:

0.00

AC:

AN:

57118

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 30, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.139C>A (p.L47I) alteration is located in exon 1 (coding exon 1) of the TLX1 gene. This alteration results from a C to A substitution at nucleotide position 139, causing the leucine (L) at amino acid position 47 to be replaced by an isoleucine (I). 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

0.16

BayesDel_addAF

Uncertain

0.037

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

T;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.76

T;T

M_CAP

Pathogenic

0.93

MetaRNN

Benign

0.35

T;T

MetaSVM

Benign

-0.44

MutationAssessor

Uncertain

2.2

M;M

PhyloP100

0.81

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.33

N;N

REVEL

Benign

0.22

Sift

Uncertain

0.011

D;D

Sift4G

Benign

0.52

T;T

Polyphen

0.61

P;.

Vest4

0.35

MutPred

0.44

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);

MVP

0.88

ClinPred

0.86

GERP RS

3.9

PromoterAI

-0.021

Neutral

(source)

Varity_R

0.19

gMVP

0.26

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over