Genetic Variant TPX2:p.Arg229Trp (chr20-31775943-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_012112.5(TPX2):c.685C>T(p.Arg229Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,574,770 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00015 ( 1 hom. )

Consequence

TPX2
NM_012112.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.82

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.022584379).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPX2	NM_012112.5 link	c.685C>T	p.Arg229Trp	missense_variant	Exon 8 of 18	ENST00000300403.11	NP_036244.2	Q9ULW0-1Q643R0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPX2	ENST00000300403.11 link	c.685C>T	p.Arg229Trp	missense_variant	Exon 8 of 18	1	NM_012112.5	ENSP00000300403.6		Q9ULW0-1
TPX2	ENST00000340513.4 link	c.685C>T	p.Arg229Trp	missense_variant	Exon 8 of 19	1		ENSP00000341145.4		Q9ULW0-2

Frequencies

GnomAD3 genomes

AF:

0.000136

AC:

AN:

146656

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000248

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000141

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.000224

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000104

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000225

AC:

AN:

244922

Hom.:

AF XY:

0.000211

AC XY:

AN XY:

132678

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000905

Gnomad ASJ exome

AF:

0.00343

Gnomad EAS exome

AF:

0.000347

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000899

Gnomad OTH exome

AF:

0.000338

GnomAD4 exome

AF:

0.000152

AC:

217

AN:

1428114

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

105

AN XY:

710132

show subpopulations

Gnomad4 AFR exome

AF:

0.000122

Gnomad4 AMR exome

AF:

0.0000466

Gnomad4 ASJ exome

AF:

0.00387

Gnomad4 EAS exome

AF:

0.000191

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000779

Gnomad4 OTH exome

AF:

0.000343

GnomAD4 genome

AF:

0.000136

AC:

AN:

146656

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

70916

show subpopulations

Gnomad4 AFR

AF:

0.0000248

Gnomad4 AMR

AF:

0.000141

Gnomad4 ASJ

AF:

0.00260

Gnomad4 EAS

AF:

0.000224

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000104

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000329

Hom.:

Bravo

AF:

0.000166

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000189

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 14, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.685C>T (p.R229W) alteration is located in exon 8 (coding exon 6) of the TPX2 gene. This alteration results from a C to T substitution at nucleotide position 685, causing the arginine (R) at amino acid position 229 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;.

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.023

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.7

D;D

REVEL

Benign

0.21

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.015

D;D

Polyphen

1.0

D;.

Vest4

0.34

MVP

0.25

MPC

0.13

ClinPred

0.21

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.18

gMVP

0.27

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over