Genetic Variant TLX1:p.His146Arg (chr10-101131978-A-G) – 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.437A>G(p.His146Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000221 in 1,355,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H146P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

TLX1
NM_005521.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.69

Publications

0 publications found

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=0.35449082).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLX1	NM_005521.4 link	c.437A>G	p.His146Arg	missense_variant	Exon 1 of 3	ENST00000370196.11	NP_005512.1	P31314-1
TLX1	NM_001195517.2 link	c.437A>G	p.His146Arg	missense_variant	Exon 1 of 3		NP_001182446.1	P31314-2
TLX1	XM_011539744.4 link	c.437A>G	p.His146Arg	missense_variant	Exon 1 of 3		XP_011538046.1
TLX1NB	NR_130724.1 link	n.580-4880T>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLX1	ENST00000370196.11 link	c.437A>G	p.His146Arg	missense_variant	Exon 1 of 3	1	NM_005521.4	ENSP00000359215.6		P31314-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000221

AC:

AN:

1355498

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

671700

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28114

American (AMR)

AF:

0.00

AC:

AN:

32680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23334

East Asian (EAS)

AF:

0.00

AC:

AN:

31804

South Asian (SAS)

AF:

0.00

AC:

AN:

74960

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5474

European-Non Finnish (NFE)

AF:

0.00000281

AC:

AN:

1066818

Other (OTH)

AF:

0.00

AC:

AN:

55952

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

T;.;.

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.035

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.66

T;T;T

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.35

T;T;T

MetaSVM

Benign

-0.47

MutationAssessor

Benign

1.6

L;L;.

PhyloP100

3.7

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-1.0

N;N;.

REVEL

Benign

0.22

Sift

Benign

0.091

T;T;.

Sift4G

Benign

0.19

T;T;T

Polyphen

0.70

P;.;.

Vest4

0.25

MutPred

0.26

Gain of MoRF binding (P = 0.0344);Gain of MoRF binding (P = 0.0344);.;

MVP

0.85

ClinPred

0.67

GERP RS

4.4

PromoterAI

-0.058

Neutral

(source)

Varity_R

0.17

gMVP

0.31

Mutation Taster

=88/12

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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chr10-101131978-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

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