X-111216481-G-A

Position:

• chrX-111216481-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_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. 13/20 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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.57

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PAK3. . Gene score misZ 3.5336 (greater than the threshold 3.09). GenCC has associacion of gene with intellectual disability, X-linked 30, non-syndromic X-linked intellectual disability, X-linked syndromic intellectual disability.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1819154).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAK3	NM_002578.5	c.1468G>A	p.Ala490Thr	missense_variant	17/18	ENST00000372007.10	NP_002569.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAK3	ENST00000372007.10	c.1468G>A	p.Ala490Thr	missense_variant	17/18	1	NM_002578.5	ENSP00000361077	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1066660 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 334868

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 21, 2015

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 15, 2023

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. 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. 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.094	.;.;T;.;.;.;.;.;T;T
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.85	.;D;.;.;.;.;D;D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.0	.;.;L;.;.;.;.;.;L;.
MutationTaster	Benign	0.89	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.36	N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.060
Sift	Benign	0.12	T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.19	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;B;B;B;B;.
Vest4		0.17
MutPred		0.23		.;.;Gain of phosphorylation at A505 (P = 0.0274);.;.;.;.;.;Gain of phosphorylation at A505 (P = 0.0274);.;
MVP		0.64
MPC		0.56
ClinPred		0.32	T
GERP RS		2.7
Varity_R		0.23
gMVP		0.38

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

Other links and lift over

dbSNP: rs1295610191; hg19: chrX-110459709;