X-111123185-C-T

Position:

• chrX-111123185-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_002578.5(PAK3):​c.82C>T​(p.Leu28Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,090,141 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 2 hem.)
• Consequence: PAK3 NM_002578.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.71

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 -5 ACMG points.

• 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=0.24455115).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAK3	NM_002578.5	c.82C>T	p.Leu28Phe	missense_variant	5/18	ENST00000372007.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAK3	ENST00000372007.10	c.82C>T	p.Leu28Phe	missense_variant	5/18	1	NM_002578.5	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1090141 Hom.: 0 Cov.: 28 AF XY: 0.00000562 AC XY: 2 AN XY: 355827

Gnomad4 AFR exome AF: 0.0000381

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: 0.00000120

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

Oct 22, 2021

This variant has not been reported in the literature in individuals affected with PAK3-related conditions. 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. 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"). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with phenylalanine at codon 28 of the PAK3 protein (p.Leu28Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	.;.;T;.;.;.;T;.;.;T
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	.;D;.;.;.;.;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.3	M;M;M;M;M;M;.;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.5	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.33	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.71	T;T;T;T;T;T;T;T;T;T
Polyphen		0.21	B;B;B;B;B;P;.;B;P;B
Vest4		0.29
MutPred		0.075		Loss of MoRF binding (P = 0.1373);Loss of MoRF binding (P = 0.1373);Loss of MoRF binding (P = 0.1373);Loss of MoRF binding (P = 0.1373);Loss of MoRF binding (P = 0.1373);Loss of MoRF binding (P = 0.1373);Loss of MoRF binding (P = 0.1373);Loss of MoRF binding (P = 0.1373);Loss of MoRF binding (P = 0.1373);Loss of MoRF binding (P = 0.1373);
MVP		0.78
MPC		1.1
ClinPred		0.76	D
GERP RS		5.6
Varity_R		0.32
gMVP		0.57

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-110366413;