Genetic Variant TLX2:p.Pro90Leu (chr2-74515075-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016170.5(TLX2):c.269C>T(p.Pro90Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000582 in 1,373,400 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000058 ( 0 hom. )

Consequence

TLX2
NM_016170.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.26

Publications

0 publications found

Variant links:

Genes affected

TLX2 (HGNC:5057): (T cell leukemia homeobox 2) This gene is a member of an orphan homeobox-containing transcription factor family. Studies of the mouse ortholog have shown that the encoded protein is crucial for the development of the enteric nervous system; in humans, loss-of-function may play a role in tumorigenesis of gastrointestinal stromal tumors. [provided by RefSeq, May 2010]

TLX2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016170.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLX2	NM_016170.5	MANE Select	c.269C>T	p.Pro90Leu	missense	Exon 1 of 3	NP_057254.1	O43763

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TLX2	ENST00000233638.8	TSL:1 MANE Select	c.269C>T	p.Pro90Leu	missense	Exon 1 of 3	ENSP00000233638.6	O43763
TLX2	ENST00000621092.1	TSL:1	c.12-558C>T		intron	N/A	ENSP00000482690.1	F1T0F2
TLX2	ENST00000497238.1	TSL:5	n.575C>T		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000857

AC:

AN:

116750

AF XY:

0.0000154

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000485

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:

0.00000582

AC:

AN:

1373400

Hom.:

Cov.:

AF XY:

0.00000443

AC XY:

AN XY:

677274

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28168

American (AMR)

AF:

0.00

AC:

AN:

31968

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24154

East Asian (EAS)

AF:

0.00

AC:

AN:

33294

South Asian (SAS)

AF:

0.00

AC:

AN:

77454

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45638

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5340

European-Non Finnish (NFE)

AF:

0.00000747

AC:

AN:

1070550

Other (OTH)

AF:

0.00

AC:

AN:

56834

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

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

0.13

BayesDel_addAF

Uncertain

0.017

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

Eigen

Uncertain

0.29

Eigen_PC

Benign

0.17

FATHMM_MKL

Benign

0.50

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.85

MetaRNN

Uncertain

0.53

MetaSVM

Uncertain

0.70

MutationAssessor

Uncertain

2.2

PhyloP100

1.3

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.45

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.014

Polyphen

1.0

Vest4

0.17

MutPred

0.20

Loss of glycosylation at P90 (P = 0.0455)

MVP

0.92

MPC

2.2

ClinPred

0.94

GERP RS

4.2

Varity_R

0.23

gMVP

0.75

Mutation Taster

=82/18

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

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over