NM_002578.5:c.830+5132A>G

Variant names:

• chrX-111178213-A-G
• rs10521534
• NM_002578.5:c.830+5132A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002578.5(PAK3):​c.830+5132A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 110,677 control chromosomes in the GnomAD database, including 2,557 homozygotes. There are 4,493 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.15 (2557 hom., 4493 hem., cov: 22)
• Consequence: PAK3 NM_002578.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.230
• Publications: 1 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: 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAK3	NM_002578.5	c.830+5132A>G		intron_variant	Intron 11 of 17	ENST00000372007.10	NP_002569.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAK3	ENST00000372007.10	c.830+5132A>G		intron_variant	Intron 11 of 17	1	NM_002578.5	ENSP00000361077.4

Frequencies

GnomAD3 genomes AF: 0.150 AC: 16557 AN: 110622 Hom.: 2555 Cov.: 22

Gnomad AFR AF: 0.472

Gnomad AMI AF: 0.00293

Gnomad AMR AF: 0.0816

Gnomad ASJ AF: 0.0114

Gnomad EAS AF: 0.00113

Gnomad SAS AF: 0.0272

Gnomad FIN AF: 0.0117

Gnomad MID AF: 0.106

Gnomad NFE AF: 0.0201

Gnomad OTH AF: 0.129

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.150 AC: 16594 AN: 110677 Hom.: 2557 Cov.: 22 AF XY: 0.136 AC XY: 4493 AN XY: 33049

African (AFR) AF: 0.472 AC: 14298 AN: 30262

American (AMR) AF: 0.0814 AC: 847 AN: 10401

Ashkenazi Jewish (ASJ) AF: 0.0114 AC: 30 AN: 2641

East Asian (EAS) AF: 0.00113 AC: 4 AN: 3525

South Asian (SAS) AF: 0.0265 AC: 69 AN: 2600

European-Finnish (FIN) AF: 0.0117 AC: 70 AN: 5998

Middle Eastern (MID) AF: 0.107 AC: 23 AN: 214

European-Non Finnish (NFE) AF: 0.0201 AC: 1060 AN: 52843

Other (OTH) AF: 0.126 AC: 191 AN: 1511

Alfa AF: 0.107 Hom.: 893

Bravo AF: 0.172

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.2
DANN	Benign	0.67
PhyloP100		-0.23
Mutation Taster		=100/0	polymorphism (auto)

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: rs10521534; hg19: chrX-110421441;