rs200474454

Variant names:

• chrX-111220391-A-G
• rs200474454
• NM_002578.5:c.1579A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. 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
• Publications: 5 publications found

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• 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

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• 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 VariationId is 431711.
• BS2: High Hemizygotes in GnomAd4 at 11 XL gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAK3	NM_002578.5	MANE Select	c.1579A>G	p.Ser527Gly	missense	Exon 18 of 18	NP_002569.1	O75914-2
	PAK3	NM_001128168.3		c.1687A>G	p.Ser563Gly	missense	Exon 20 of 20	NP_001121640.1	O75914-3
	PAK3	NM_001128172.2		c.1642A>G	p.Ser548Gly	missense	Exon 15 of 15	NP_001121644.1	O75914-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAK3	ENST00000372007.10	TSL:1 MANE Select	c.1579A>G	p.Ser527Gly	missense	Exon 18 of 18	ENSP00000361077.4	O75914-2
	PAK3	ENST00000360648.8	TSL:1	c.1687A>G	p.Ser563Gly	missense	Exon 16 of 16	ENSP00000353864.4	O75914-3
	PAK3	ENST00000417227.5	TSL:1	c.1642A>G	p.Ser548Gly	missense	Exon 15 of 15	ENSP00000389172.1	O75914-4

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 22 AN: 111421 Hom.: 0 Cov.: 22

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

GnomAD2 exomes AF: 0.000148 AC: 27 AN: 182204 AF XY: 0.000120

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 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

African (AFR) AF: 0.0000761 AC: 2 AN: 26295

American (AMR) AF: 0.0000284 AC: 1 AN: 35178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19349

East Asian (EAS) AF: 0.00 AC: 0 AN: 30174

South Asian (SAS) AF: 0.00 AC: 0 AN: 53929

European-Finnish (FIN) AF: 0.000840 AC: 34 AN: 40488

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4121

European-Non Finnish (NFE) AF: 0.000217 AC: 182 AN: 836932

Other (OTH) AF: 0.000261 AC: 12 AN: 45919

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

African (AFR) AF: 0.00 AC: 0 AN: 30656

American (AMR) AF: 0.00 AC: 0 AN: 10468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3541

South Asian (SAS) AF: 0.00 AC: 0 AN: 2595

European-Finnish (FIN) AF: 0.00134 AC: 8 AN: 5991

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.000263 AC: 14 AN: 53141

Other (OTH) AF: 0.00 AC: 0 AN: 1531

Alfa AF: 0.000209 Hom.: 7

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Intellectual disability, X-linked 30 (3)
-	1	1	not provided (2)
-	-	1	not specified (1)
-	-	1	PAK3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.37	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.6	L
PhyloP100		8.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.065	T
Polyphen		1.0	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
Mutation Taster		=12/88	disease causing

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

Other links and lift over

dbSNP: rs200474454; hg19: chrX-110463619; COSMIC: COSV107297558;