X-111162977-GGAA-GGAAGAA

Position:

• chrX-111162977-GGAA-GGAAGAA

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The ENST00000372007.10(PAK3):​c.546_548dup​(p.Glu182dup) variant causes a inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000749 in 1,201,583 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 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. E177E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.0000037 (0 hom. 2 hem.)
• Consequence: PAK3 ENST00000372007.10 inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.19

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BS2: High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAK3	NM_002578.5	c.546_548dup	p.Glu182dup	inframe_insertion	9/18	ENST00000372007.10	NP_002569.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAK3	ENST00000372007.10	c.546_548dup	p.Glu182dup	inframe_insertion	9/18	1	NM_002578.5	ENSP00000361077	P1

Frequencies

GnomAD3 genomes AF: 0.0000451 AC: 5 AN: 110903 Hom.: 0 Cov.: 23 AF XY: 0.0000903 AC XY: 3 AN XY: 33209

Gnomad AFR AF: 0.0000981

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000378

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000332 AC: 6 AN: 180542 Hom.: 0 AF XY: 0.0000300 AC XY: 2 AN XY: 66746

Gnomad AFR exome AF: 0.000305

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000252

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000367 AC: 4 AN: 1090680 Hom.: 0 Cov.: 28 AF XY: 0.00000561 AC XY: 2 AN XY: 356686

Gnomad4 AFR exome AF: 0.0000762

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000239

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000451 AC: 5 AN: 110903 Hom.: 0 Cov.: 23 AF XY: 0.0000903 AC XY: 3 AN XY: 33209

Gnomad4 AFR AF: 0.0000981

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000378

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs749370794; hg19: chrX-110406205;