Genetic Variant TLX1:p.Thr66Ala (chr10-101131737-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005521.4(TLX1):c.196A>G(p.Thr66Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000278 in 1,436,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. T66P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

TLX1
NM_005521.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.283

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15600094).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLX1	NM_005521.4 link	c.196A>G	p.Thr66Ala	missense_variant	Exon 1 of 3	ENST00000370196.11	NP_005512.1	P31314-1
TLX1	NM_001195517.2 link	c.196A>G	p.Thr66Ala	missense_variant	Exon 1 of 3		NP_001182446.1	P31314-2
TLX1	XM_011539744.4 link	c.196A>G	p.Thr66Ala	missense_variant	Exon 1 of 3		XP_011538046.1
TLX1NB	NR_130724.1 link	n.580-4639T>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.196A>G	p.Thr66Ala	missense_variant	Exon 1 of 3	1	NM_005521.4	ENSP00000359215.6		P31314-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151740

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000578

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:

0.00

GnomAD4 exome

AF:

0.00000156

AC:

AN:

1284744

Hom.:

Cov.:

AF XY:

0.00000318

AC XY:

AN XY:

629542

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25272

American (AMR)

AF:

0.00

AC:

AN:

17004

Ashkenazi Jewish (ASJ)

AF:

0.0000547

AC:

AN:

18284

East Asian (EAS)

AF:

0.00

AC:

AN:

29700

South Asian (SAS)

AF:

0.00

AC:

AN:

60004

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43742

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5110

European-Non Finnish (NFE)

AF:

9.68e-7

AC:

AN:

1032874

Other (OTH)

AF:

0.00

AC:

AN:

52754

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

AF:

0.0000132

AC:

AN:

151740

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74112

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41308

American (AMR)

AF:

0.00

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.000578

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5136

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10556

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67918

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.050

BayesDel_noAF

Benign

-0.31

CADD

Benign

0.81

(source)

DANN

Benign

0.30

DEOGEN2

Benign

0.20

T;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0055

LIST_S2

Benign

0.15

T;T;T

M_CAP

Pathogenic

0.86

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

-0.34

N;N;.

PhyloP100

-0.28

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.090

N;N;.

REVEL

Benign

0.21

Sift

Benign

0.61

T;T;.

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.086

MutPred

0.26

Loss of glycosylation at T66 (P = 0.0046);Loss of glycosylation at T66 (P = 0.0046);.;

MVP

0.56

ClinPred

0.032

GERP RS

3.5

PromoterAI

0.051

Neutral

(source)

Varity_R

0.052

gMVP

0.13

Mutation Taster

=97/3

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

Computational scores

Splicing

Publications

Other links and lift over