dbSNP rs771264707: TPX2:p.Leu238Ile (chr20-31775970-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_012112.5(TPX2):c.712C>A(p.Leu238Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000741 in 1,348,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. L238R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

TPX2
NM_012112.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.627

Publications

0 publications found

Variant links:

Genes affected

TPX2 (HGNC:1249): (TPX2 microtubule nucleation factor) Enables importin-alpha family protein binding activity and protein kinase binding activity. Involved in activation of protein kinase activity; microtubule cytoskeleton organization; and negative regulation of microtubule depolymerization. Located in intercellular bridge; mitotic spindle; and nucleoplasm. Colocalizes with spindle pole. [provided by Alliance of Genome Resources, Apr 2022]

TPX2 Gene-Disease associations (from GenCC):

Tourette syndrome
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

TPX2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04180184).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012112.5. 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
	TPX2	NM_012112.5	MANE Select	c.712C>A	p.Leu238Ile	missense	Exon 8 of 18	NP_036244.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TPX2	ENST00000300403.11	TSL:1 MANE Select	c.712C>A	p.Leu238Ile	missense	Exon 8 of 18	ENSP00000300403.6	Q9ULW0-1
TPX2	ENST00000340513.4	TSL:1	c.712C>A	p.Leu238Ile	missense	Exon 8 of 19	ENSP00000341145.4	Q9ULW0-2
TPX2	ENST00000934062.1		c.712C>A	p.Leu238Ile	missense	Exon 8 of 19	ENSP00000604121.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.41e-7

AC:

AN:

1348622

Hom.:

Cov.:

AF XY:

0.00000149

AC XY:

AN XY:

669476

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31716

American (AMR)

AF:

0.00

AC:

AN:

39904

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22376

East Asian (EAS)

AF:

0.00

AC:

AN:

26756

South Asian (SAS)

AF:

0.00

AC:

AN:

82598

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45850

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5188

European-Non Finnish (NFE)

AF:

9.61e-7

AC:

AN:

1040942

Other (OTH)

AF:

0.00

AC:

AN:

53292

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.023

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.78

M_CAP

Benign

0.0038

MetaRNN

Benign

0.042

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PhyloP100

0.63

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.34

REVEL

Benign

0.054

Sift

Benign

0.29

Sift4G

Benign

0.59

Polyphen

0.0010

Vest4

0.14

MutPred

0.22

Gain of methylation at K236 (P = 0.1441)

MVP

0.082

MPC

0.12

ClinPred

0.12

GERP RS

-3.4

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.024

gMVP

0.10

Mutation Taster

=99/1

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over