Genetic Variant TPX2:p.Glu277Ala (chr20-31777586-A-C) – 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_012112.5(TPX2):c.830A>C(p.Glu277Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. E277V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TPX2
NM_012112.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.23

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:

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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=0.2467455).

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.830A>C	p.Glu277Ala	missense	Exon 9 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.830A>C	p.Glu277Ala	missense	Exon 9 of 18	ENSP00000300403.6	Q9ULW0-1
TPX2	ENST00000340513.4	TSL:1	c.830A>C	p.Glu277Ala	missense	Exon 9 of 19	ENSP00000341145.4	Q9ULW0-2
TPX2	ENST00000934062.1		c.830A>C	p.Glu277Ala	missense	Exon 9 of 19	ENSP00000604121.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251434

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111994

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.056

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.74

M_CAP

Benign

0.015

MetaRNN

Benign

0.25

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.5

PhyloP100

3.2

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-2.0

REVEL

Benign

0.082

Sift

Benign

0.046

Sift4G

Uncertain

0.053

Polyphen

0.98

Vest4

0.53

MutPred

0.17

Loss of ubiquitination at K279 (P = 0.0331)

MVP

0.28

MPC

0.17

ClinPred

0.73

GERP RS

4.2

Varity_R

0.085

gMVP

0.16

Mutation Taster

=87/13

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over