rs200474454

chrX-111220391-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 3P and 7B. PM1 PP2 BP4_Moderate BP6 BS2

The NM_002578.5(PAK3):c.1579A>G(p.Ser527Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00021 in 1,203,860 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 76 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., 11 hem., cov: 22)
  • Exomes 𝑓: 0.00021 (0 hom. 65 hem.)
• Consequence: PAK3 NM_002578.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 8.89

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 Likely_benign. Variant got -4 ACMG points.

• PM1: In a domain Protein kinase (size 251) in uniprot entity PAK3_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_002578.5
• PP2: Missense variant where missense usually causes diseases, PAK3
• BP4: Computational evidence support a benign effect (MetaRNN=0.11277586).
• BP6: Variant X-111220391-A-G is Benign according to our data. Variant chrX-111220391-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 431711.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=1, Likely_benign=3}.
• BS2: High Hemizygotes in GnomAd at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAK3	NM_002578.5	c.1579A>G	p.Ser527Gly	missense_variant	18/18	ENST00000372007.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAK3	ENST00000372007.10	c.1579A>G	p.Ser527Gly	missense_variant	18/18	1	NM_002578.5	P1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 22 AN: 111421 Hom.: 0 Cov.: 22 AF XY: 0.000327 AC XY: 11 AN XY: 33603

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: 0.00

Gnomad FIN AF: 0.00134

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000263

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000148 AC: 27 AN: 182204 Hom.: 0 AF XY: 0.000120 AC XY: 8 AN XY: 66776

Gnomad AFR exome AF: 0.0000765

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00113

Gnomad NFE exome AF: 0.0000984

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000211 AC: 231 AN: 1092385 Hom.: 0 Cov.: 27 AF XY: 0.000182 AC XY: 65 AN XY: 358061

Gnomad4 AFR exome AF: 0.0000761

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000840

Gnomad4 NFE exome AF: 0.000217

Gnomad4 OTH exome AF: 0.000261

GnomAD4 genome AF: 0.000197 AC: 22 AN: 111475 Hom.: 0 Cov.: 22 AF XY: 0.000327 AC XY: 11 AN XY: 33667

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00134

Gnomad4 NFE AF: 0.000263

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000220 Hom.: 6

Bravo AF: 0.000132

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000173 AC: 21

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, X-linked 30 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 20, 2022	- -
Uncertain significance, criteria provided, single submitter	research	TIDEX, University of British Columbia	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Aug 22, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 04, 2023

Variant summary: PAK3 c.1579A>G (p.Ser527Gly) results in a non-conservative amino acid change located in the p21-activated kinase 3, catalytic domain (IPR035063) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 204029 control chromosomes (gnomAD), predominantly at a frequency of 0.0012 within the Finnish subpopulation in the gnomAD database, including 9 hemizygotes. c.1579A>G has been reported in the literature in individuals affected with intellectual disability or atypical cerebral palsy (Tzschach_2015, Horvath_2018, Matthews_2018). These reports do not provide unequivocal conclusions about association of the variant with Intellectual Disability, X-Linked 30. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31843706, 29246092, 30542205, 32050918, 25649377). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=2), likely benign (n=1) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

PAK3-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 26, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Uncertain	0.060
Cadd	Pathogenic	26
Dann	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.20	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D;D;D;D;D;.
REVEL	Uncertain	0.49
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;.
Sift4G	Benign	0.065	T;T;T;T;T;T;T;T;T;T
Polyphen		1.0	D;D;D;D;D;D;D;D;D;.
Vest4		0.56
MVP		0.93
MPC		1.5
ClinPred		0.32	T
GERP RS		6.2
Varity_R		0.92
gMVP		0.49

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: rs200474454; hg19: chrX-110463619;