X-111162977-GGAA-GGAAGAAGAA

Variant names:

• chrX-111162977-G-GGAAGAA
• rs749370794
• NM_002578.5:c.543_548dupAGAAGA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3 BP3 BS2

The NM_002578.5(PAK3):​c.543_548dupAGAAGA​(p.Glu181_Glu182dup) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000128 in 1,090,699 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D183D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000013 (0 hom. 9 hem.)
• Consequence: PAK3 NM_002578.5 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.19
• 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Likely_benign. The variant received -4 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP3: Nonframeshift variant in repetitive region in NM_002578.5
• BS2: High Hemizygotes in GnomAdExome4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAK3	NM_002578.5	c.543_548dupAGAAGA	p.Glu181_Glu182dup	disruptive_inframe_insertion	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.543_548dupAGAAGA	p.Glu181_Glu182dup	disruptive_inframe_insertion	Exon 9 of 18	1	NM_002578.5	ENSP00000361077.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.0000128 AC: 14 AN: 1090699 Hom.: 0 Cov.: 28 AF XY: 0.0000252 AC XY: 9 AN XY: 356697

African (AFR) AF: 0.00 AC: 0 AN: 26248

American (AMR) AF: 0.00 AC: 0 AN: 35174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19322

East Asian (EAS) AF: 0.00 AC: 0 AN: 30162

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 53961

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4112

European-Non Finnish (NFE) AF: 0.0000156 AC: 13 AN: 835348

Other (OTH) AF: 0.00 AC: 0 AN: 45854

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.2

Splicing

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

Other links and lift over

dbSNP: rs749370794; hg19: chrX-110406205;