X-111196488-C-T

Variant names:

• chrX-111196488-C-T
• rs121434611
• NM_002578.5:c.1255C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_002578.5(PAK3):​c.1255C>T​(p.Arg419*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. R419R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: PAK3 NM_002578.5 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 3.72
• Publications: 7 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-111196488-C-T is Pathogenic according to our data. Variant chrX-111196488-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 11568.Status of the report is no_assertion_criteria_provided, 0 stars.

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.1255C>T	p.Arg419*	stop_gained	Exon 16 of 18	NP_002569.1	O75914-2
	PAK3	NM_001128168.3		c.1363C>T	p.Arg455*	stop_gained	Exon 18 of 20	NP_001121640.1	O75914-3
	PAK3	NM_001128172.2		c.1318C>T	p.Arg440*	stop_gained	Exon 13 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.1255C>T	p.Arg419*	stop_gained	Exon 16 of 18	ENSP00000361077.4	O75914-2
	PAK3	ENST00000360648.8	TSL:1	c.1363C>T	p.Arg455*	stop_gained	Exon 14 of 16	ENSP00000353864.4	O75914-3
	PAK3	ENST00000417227.5	TSL:1	c.1318C>T	p.Arg440*	stop_gained	Exon 13 of 15	ENSP00000389172.1	O75914-4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual disability, X-linked 30 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		3.7
Vest4		0.83
GERP RS		4.5
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs121434611; hg19: chrX-110439716; COSMIC: COSV53273940;