Genetic Variant TLX1:p.Ala145Val (chr10-101131975-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -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. 14/22 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

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

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

BS2

High AC in GnomAd4 at 65 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005521.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TLX1	NM_005521.4	MANE Select	c.434C>T	p.Ala145Val	missense	Exon 1 of 3	NP_005512.1	P31314-1
TLX1	NM_001195517.2		c.434C>T	p.Ala145Val	missense	Exon 1 of 3	NP_001182446.1	P31314-2
TLX1NB	NR_130724.1		n.580-4877G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TLX1	ENST00000370196.11	TSL:1 MANE Select	c.434C>T	p.Ala145Val	missense	Exon 1 of 3	ENSP00000359215.6	P31314-1
TLX1	ENST00000467928.2	TSL:1	c.434C>T	p.Ala145Val	missense	Exon 1 of 3	ENSP00000434914.2	P31314-2
TLX1	ENST00000463716.3	TSL:3	c.248C>T	p.Ala83Val	missense	Exon 1 of 2	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

GnomAD2 exomes

AF:

0.0000736

AC:

AN:

163006

AF XY:

0.0000323

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 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

African (AFR)

AF:

0.00192

AC:

AN:

28096

American (AMR)

AF:

0.000122

AC:

AN:

32730

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23376

East Asian (EAS)

AF:

0.00

AC:

AN:

31792

South Asian (SAS)

AF:

0.0000133

AC:

AN:

75124

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36328

Middle Eastern (MID)

AF:

0.000365

AC:

AN:

5484

European-Non Finnish (NFE)

AF:

0.00000187

AC:

AN:

1067696

Other (OTH)

AF:

0.000107

AC:

AN:

56026

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000427

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.00154

AC:

AN:

41550

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67964

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.74

M_CAP

Pathogenic

0.70

MetaRNN

Benign

0.020

MetaSVM

Benign

-0.29

MutationAssessor

Benign

1.1

PhyloP100

2.3

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.30

REVEL

Benign

0.20

Sift

Benign

0.030

Sift4G

Benign

0.33

Polyphen

0.36

Vest4

0.12

MVP

0.95

ClinPred

0.035

GERP RS

4.2

PromoterAI

-0.028

Neutral

(source)

Varity_R

0.14

gMVP

0.19

Mutation Taster

=85/15

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over