X-111123124-T-G

Position:

• chrX-111123124-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_002578.5(PAK3):​c.21T>G​(p.Asn7Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: PAK3 NM_002578.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.88

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PAK3. . Gene score misZ 3.5336 (greater than the threshold 3.09). GenCC has associacion of gene with intellectual disability, X-linked 30, non-syndromic X-linked intellectual disability, X-linked syndromic intellectual disability.
• BP4: Computational evidence support a benign effect (MetaRNN=0.12629542).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAK3	NM_002578.5	c.21T>G	p.Asn7Lys	missense_variant	5/18	ENST00000372007.10	NP_002569.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAK3	ENST00000372007.10	c.21T>G	p.Asn7Lys	missense_variant	5/18	1	NM_002578.5	ENSP00000361077	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183165 Hom.: 0 AF XY: 0.0000148 AC XY: 1 AN XY: 67703

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.15e-7 AC: 1 AN: 1092973 Hom.: 0 Cov.: 28 AF XY: 0.00000279 AC XY: 1 AN XY: 358511

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 29, 2022

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 7 of the PAK3 protein (p.Asn7Lys). This variant is present in population databases (no rsID available, gnomAD 0.004%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with PAK3-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	19
DANN	Benign	0.70
DEOGEN2	Benign	0.10	.;.;T;.;.;.;T;.;.;T;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	.;T;.;.;.;.;D;D;D;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.0	N;N;N;N;N;N;.;N;N;N;.
MutationTaster	Benign	0.69	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.54	N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.064
Sift	Benign	0.33	T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.92	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0020	B;B;B;B;B;B;.;B;B;B;.
Vest4		0.25
MutPred		0.19		Gain of ubiquitination at N7 (P = 0.0037);Gain of ubiquitination at N7 (P = 0.0037);Gain of ubiquitination at N7 (P = 0.0037);Gain of ubiquitination at N7 (P = 0.0037);Gain of ubiquitination at N7 (P = 0.0037);Gain of ubiquitination at N7 (P = 0.0037);Gain of ubiquitination at N7 (P = 0.0037);Gain of ubiquitination at N7 (P = 0.0037);Gain of ubiquitination at N7 (P = 0.0037);Gain of ubiquitination at N7 (P = 0.0037);Gain of ubiquitination at N7 (P = 0.0037);
MVP		0.74
MPC		1.1
ClinPred		0.061	T
GERP RS		4.0
Varity_R		0.12
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1189894083; hg19: chrX-110366352;