rs56270341

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 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 -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 Benign/Likely_benign. ClinVar VariationId 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

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.531G>A	p.Glu177Glu	synonymous	Exon 9 of 18	NP_002569.1	O75914-2
	PAK3	NM_001128168.3		c.639G>A	p.Glu213Glu	synonymous	Exon 11 of 20	NP_001121640.1	O75914-3
	PAK3	NM_001128172.2		c.594G>A	p.Glu198Glu	synonymous	Exon 6 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.531G>A	p.Glu177Glu	synonymous	Exon 9 of 18	ENSP00000361077.4	O75914-2
	PAK3	ENST00000360648.8	TSL:1	c.639G>A	p.Glu213Glu	synonymous	Exon 7 of 16	ENSP00000353864.4	O75914-3
	PAK3	ENST00000417227.5	TSL:1	c.594G>A	p.Glu198Glu	synonymous	Exon 6 of 15	ENSP00000389172.1	O75914-4

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 263 AN: 110903 Hom.: 0 Cov.: 23

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

GnomAD2 exomes AF: 0.00237 AC: 428 AN: 180542 AF XY: 0.00228

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 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

African (AFR) AF: 0.000495 AC: 13 AN: 26248

American (AMR) AF: 0.000256 AC: 9 AN: 35174

Ashkenazi Jewish (ASJ) AF: 0.00114 AC: 22 AN: 19322

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30162

South Asian (SAS) AF: 0.00196 AC: 106 AN: 53957

European-Finnish (FIN) AF: 0.00220 AC: 89 AN: 40517

Middle Eastern (MID) AF: 0.00122 AC: 5 AN: 4112

European-Non Finnish (NFE) AF: 0.00394 AC: 3289 AN: 835312

Other (OTH) AF: 0.00290 AC: 133 AN: 45852

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

African (AFR) AF: 0.000424 AC: 13 AN: 30633

American (AMR) AF: 0.00 AC: 0 AN: 10359

Ashkenazi Jewish (ASJ) AF: 0.00152 AC: 4 AN: 2635

East Asian (EAS) AF: 0.00 AC: 0 AN: 3518

South Asian (SAS) AF: 0.000766 AC: 2 AN: 2611

European-Finnish (FIN) AF: 0.00302 AC: 18 AN: 5963

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00426 AC: 225 AN: 52835

Other (OTH) AF: 0.000668 AC: 1 AN: 1498

Alfa AF: 0.00206 Hom.: 25

Bravo AF: 0.00211

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	History of neurodevelopmental disorder (1)
-	-	1	Intellectual disability, X-linked 30 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	1.5
DANN	Benign	0.47
PhyloP100		-0.61
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: rs56270341; hg19: chrX-110406205;