rs56270341

Variant names:

• chrX-111162977-G-A
• rs56270341
• NM_002578.5:c.531G>A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_002578.5(PAK3):​c.531G>A​(p.Glu177Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00327 in 1,201,610 control chromosomes in the GnomAD database, including 6 homozygotes. There are 1,172 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., 70 hem., cov: 23)
  • Exomes 𝑓: 0.0034 (6 hom. 1102 hem.)
• Consequence: PAK3 NM_002578.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.612

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant X-111162977-G-A is Benign according to our data. Variant chrX-111162977-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 211837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.612 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 70 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAK3	NM_002578.5	c.531G>A	p.Glu177Glu	synonymous_variant	Exon 9 of 18	ENST00000372007.10	NP_002569.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAK3	ENST00000372007.10	c.531G>A	p.Glu177Glu	synonymous_variant	Exon 9 of 18	1	NM_002578.5	ENSP00000361077.4

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 263 AN: 110903 Hom.: 0 Cov.: 23 AF XY: 0.00211 AC XY: 70 AN XY: 33209

Gnomad AFR AF: 0.000425

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00152

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000764

Gnomad FIN AF: 0.00302

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00426

Gnomad OTH AF: 0.000676

GnomAD3 exomes AF: 0.00237 AC: 428 AN: 180542 Hom.: 1 AF XY: 0.00228 AC XY: 152 AN XY: 66746

Gnomad AFR exome AF: 0.000609

Gnomad AMR exome AF: 0.000256

Gnomad ASJ exome AF: 0.00107

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00189

Gnomad FIN exome AF: 0.00238

Gnomad NFE exome AF: 0.00401

Gnomad OTH exome AF: 0.00289

GnomAD4 exome AF: 0.00336 AC: 3667 AN: 1090656 Hom.: 6 Cov.: 28 AF XY: 0.00309 AC XY: 1102 AN XY: 356658

Gnomad4 AFR exome AF: 0.000495

Gnomad4 AMR exome AF: 0.000256

Gnomad4 ASJ exome AF: 0.00114

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.00196

Gnomad4 FIN exome AF: 0.00220

Gnomad4 NFE exome AF: 0.00394

Gnomad4 OTH exome AF: 0.00290

GnomAD4 genome AF: 0.00237 AC: 263 AN: 110954 Hom.: 0 Cov.: 23 AF XY: 0.00210 AC XY: 70 AN XY: 33270

Gnomad4 AFR AF: 0.000424

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00152

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000766

Gnomad4 FIN AF: 0.00302

Gnomad4 NFE AF: 0.00426

Gnomad4 OTH AF: 0.000668

Alfa AF: 0.00204 Hom.: 15

Bravo AF: 0.00211

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 16, 2017

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jul 06, 2017

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability, X-linked 30 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

History of neurodevelopmental disorder Benign:1

Jul 28, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	1.5
DANN	Benign	0.47

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: rs56270341; hg19: chrX-110406205;