X-111216481-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002578.5(PAK3):c.1468G>A(p.Ala490Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

PAK3
NM_002578.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.57

Publications

1 publications found

Variant links:

Genes affected

PAK3 (HGNC:8592): (p21 (RAC1) activated kinase 3) The protein encoded by this gene is a serine-threonine kinase and forms an activated complex with GTP-bound RAS-like (P21), CDC2 and RAC1. This protein may be necessary for dendritic development and for the rapid cytoskeletal reorganization in dendritic spines associated with synaptic plasticity. Defects in this gene are the cause of a non-syndromic form of X-linked intellectual disability. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2017]

PAK3 Gene-Disease associations (from GenCC):

corpus callosum, agenesis of
Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
intellectual disability, X-linked 30
Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
X-linked syndromic intellectual disability
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
non-syndromic X-linked intellectual disability
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

PAK3 links:

Genome browser will be placed here

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=0.1819154).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002578.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PAK3	NM_002578.5	MANE Select	c.1468G>A	p.Ala490Thr	missense	Exon 17 of 18	NP_002569.1
PAK3	NM_001128168.3		c.1576G>A	p.Ala526Thr	missense	Exon 19 of 20	NP_001121640.1
PAK3	NM_001128172.2		c.1531G>A	p.Ala511Thr	missense	Exon 14 of 15	NP_001121644.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PAK3	ENST00000372007.10	TSL:1 MANE Select	c.1468G>A	p.Ala490Thr	missense	Exon 17 of 18	ENSP00000361077.4
PAK3	ENST00000360648.8	TSL:1	c.1576G>A	p.Ala526Thr	missense	Exon 15 of 16	ENSP00000353864.4
PAK3	ENST00000417227.5	TSL:1	c.1531G>A	p.Ala511Thr	missense	Exon 14 of 15	ENSP00000389172.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1066660

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

334868

African (AFR)

AF:

0.00

AC:

AN:

25865

American (AMR)

AF:

0.00

AC:

AN:

35174

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19199

East Asian (EAS)

AF:

0.00

AC:

AN:

30084

South Asian (SAS)

AF:

0.00

AC:

AN:

53370

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40517

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4057

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

813283

Other (OTH)

AF:

0.00

AC:

AN:

45111

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 21, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:1

Jun 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 436147). This variant has not been reported in the literature in individuals affected with PAK3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 490 of the PAK3 protein (p.Ala490Thr). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.094

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.85

M_CAP

Benign

0.027

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.0

PhyloP100

1.6

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.36

REVEL

Benign

0.060

Sift

Benign

0.12

Sift4G

Benign

0.19

Polyphen

0.0

Vest4

0.17

MutPred

0.23

Gain of phosphorylation at A505 (P = 0.0274)

MVP

0.64

MPC

0.56

ClinPred

0.32

GERP RS

2.7

Varity_R

0.23

gMVP

0.38

Mutation Taster

=75/25

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over