Genetic Variant TPX2:p.Asn308Lys (chr20-31778854-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012112.5(TPX2):c.924C>A(p.Asn308Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,608,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

TPX2
NM_012112.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.474

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24324656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPX2	NM_012112.5 link	c.924C>A	p.Asn308Lys	missense_variant	Exon 10 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.924C>A	p.Asn308Lys	missense_variant	Exon 10 of 18	1	NM_012112.5	ENSP00000300403.6		Q9ULW0-1
TPX2	ENST00000340513.4 link	c.924C>A	p.Asn308Lys	missense_variant	Exon 10 of 19	1		ENSP00000341145.4		Q9ULW0-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000204

AC:

AN:

245494

Hom.:

AF XY:

0.0000301

AC XY:

AN XY:

132770

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000304

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000102

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.00000481

AC:

AN:

1455826

Hom.:

Cov.:

AF XY:

0.00000690

AC XY:

AN XY:

724188

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000233

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000706

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.924C>A (p.N308K) alteration is located in exon 10 (coding exon 8) of the TPX2 gene. This alteration results from a C to A substitution at nucleotide position 924, causing the asparagine (N) at amino acid position 308 to be replaced by a lysine (K). 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

Uncertain

0.50

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.061

T;.

Eigen

Benign

0.15

Eigen_PC

Benign

0.090

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.24

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

M;M

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.8

D;D

REVEL

Benign

0.13

Sift

Benign

0.14

T;T

Sift4G

Benign

0.99

T;T

Polyphen

0.98

D;.

Vest4

0.55

MutPred

0.35

Gain of methylation at N308 (P = 0.0045);Gain of methylation at N308 (P = 0.0045);

MVP

0.43

MPC

0.50

ClinPred

0.83

GERP RS

0.78

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.40

gMVP

0.45

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