ENST00000360648.8:c.298A>T

Variant names:

• chrX-111144881-A-T
• ENST00000360648.8:c.298A>T
• PAK3 p.Arg100*

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The ENST00000360648.8(PAK3):​c.298A>T​(p.Arg100*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: PAK3 ENST00000360648.8 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.41
• 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), G2P, Ambry Genetics
• 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 10 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000360648.8. 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.276+2685A>T		intron	N/A	NP_002569.1	O75914-2
	PAK3	NM_001128168.3		c.298A>T	p.Arg100*	stop_gained	Exon 7 of 20	NP_001121640.1	O75914-3
	PAK3	NM_001128172.2		c.298A>T	p.Arg100*	stop_gained	Exon 3 of 15	NP_001121644.1	O75914-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAK3	ENST00000360648.8	TSL:1	c.298A>T	p.Arg100*	stop_gained	Exon 3 of 16	ENSP00000353864.4	O75914-3
	PAK3	ENST00000417227.5	TSL:1	c.298A>T	p.Arg100*	stop_gained	Exon 3 of 15	ENSP00000389172.1	O75914-4
	PAK3	ENST00000372007.10	TSL:1 MANE Select	c.276+2685A>T		intron	N/A	ENSP00000361077.4	O75914-2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1040581 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 321019

African (AFR) AF: 0.00 AC: 0 AN: 25321

American (AMR) AF: 0.00 AC: 0 AN: 32394

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18677

East Asian (EAS) AF: 0.00 AC: 0 AN: 29246

South Asian (SAS) AF: 0.00 AC: 0 AN: 49878

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39127

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4007

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 797914

Other (OTH) AF: 0.00 AC: 0 AN: 44017

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Benign	23
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.60	D
PhyloP100		1.4
Mutation Taster		=5/195	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-110388109;