rs146801179

Variant names:

• chrX-111162929-A-G
• rs146801179
• NM_002578.5:c.483A>G

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.483A>G​(p.Ala161Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000295 in 1,205,216 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 110 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 0.00057 (0 hom., 17 hem., cov: 23)
  • Exomes 𝑓: 0.00027 (0 hom. 93 hem.)
• Consequence: PAK3 NM_002578.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.552
• Publications: 0 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=-0.75).
• BP6: Variant X-111162929-A-G is Benign according to our data. Variant chrX-111162929-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 367714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.552 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 17 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.483A>G	p.Ala161Ala	synonymous	Exon 9 of 18	NP_002569.1	O75914-2
	PAK3	NM_001128168.3		c.591A>G	p.Ala197Ala	synonymous	Exon 11 of 20	NP_001121640.1	O75914-3
	PAK3	NM_001128172.2		c.546A>G	p.Ala182Ala	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.483A>G	p.Ala161Ala	synonymous	Exon 9 of 18	ENSP00000361077.4	O75914-2
	PAK3	ENST00000360648.8	TSL:1	c.591A>G	p.Ala197Ala	synonymous	Exon 7 of 16	ENSP00000353864.4	O75914-3
	PAK3	ENST00000417227.5	TSL:1	c.546A>G	p.Ala182Ala	synonymous	Exon 6 of 15	ENSP00000389172.1	O75914-4

Frequencies

GnomAD3 genomes AF: 0.000574 AC: 64 AN: 111491 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000192

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000170

Gnomad OTH AF: 0.00133

GnomAD2 exomes AF: 0.000375 AC: 68 AN: 181171 AF XY: 0.000358

Gnomad AFR exome AF: 0.00251

Gnomad AMR exome AF: 0.000438

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000263

Gnomad OTH exome AF: 0.000444

GnomAD4 exome AF: 0.000266 AC: 291 AN: 1093672 Hom.: 0 Cov.: 28 AF XY: 0.000259 AC XY: 93 AN XY: 359396

African (AFR) AF: 0.00255 AC: 67 AN: 26317

American (AMR) AF: 0.000483 AC: 17 AN: 35182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19327

East Asian (EAS) AF: 0.00 AC: 0 AN: 30156

South Asian (SAS) AF: 0.00 AC: 0 AN: 54040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40526

Middle Eastern (MID) AF: 0.00170 AC: 7 AN: 4123

European-Non Finnish (NFE) AF: 0.000204 AC: 171 AN: 838062

Other (OTH) AF: 0.000631 AC: 29 AN: 45939

GnomAD4 genome AF: 0.000574 AC: 64 AN: 111544 Hom.: 0 Cov.: 23 AF XY: 0.000504 AC XY: 17 AN XY: 33734

African (AFR) AF: 0.00166 AC: 51 AN: 30794

American (AMR) AF: 0.000192 AC: 2 AN: 10416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3524

South Asian (SAS) AF: 0.00 AC: 0 AN: 2633

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6065

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

European-Non Finnish (NFE) AF: 0.000170 AC: 9 AN: 53038

Other (OTH) AF: 0.00131 AC: 2 AN: 1525

Alfa AF: 0.000477 Hom.: 3

Bravo AF: 0.000722

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	4.1
DANN	Benign	0.67
PhyloP100		-0.55
Mutation Taster		=100/0	polymorphism

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: rs146801179; hg19: chrX-110406157;