chrX-111123120-A-G

Variant names:

• chrX-111123120-A-G
• NM_002578.5:c.17A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002578.5(PAK3):​c.17A>G​(p.Asp6Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PAK3 NM_002578.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.53

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAK3	NM_002578.5	c.17A>G	p.Asp6Gly	missense_variant	Exon 5 of 18	ENST00000372007.10	NP_002569.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAK3	ENST00000372007.10	c.17A>G	p.Asp6Gly	missense_variant	Exon 5 of 18	1	NM_002578.5	ENSP00000361077.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 05, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	.;.;T;.;.;.;T;.;.;T;T
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	.;D;.;.;.;.;D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.2	M;M;M;M;M;M;.;M;M;M;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.3	N;N;N;N;N;N;D;N;N;N;.
REVEL	Uncertain	0.47
Sift	Benign	0.054	T;T;D;D;T;D;D;D;D;D;.
Sift4G	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;B;.;B;B;B;.
Vest4		0.47
MutPred		0.072		Gain of glycosylation at K10 (P = 0.2191);Gain of glycosylation at K10 (P = 0.2191);Gain of glycosylation at K10 (P = 0.2191);Gain of glycosylation at K10 (P = 0.2191);Gain of glycosylation at K10 (P = 0.2191);Gain of glycosylation at K10 (P = 0.2191);Gain of glycosylation at K10 (P = 0.2191);Gain of glycosylation at K10 (P = 0.2191);Gain of glycosylation at K10 (P = 0.2191);Gain of glycosylation at K10 (P = 0.2191);Gain of glycosylation at K10 (P = 0.2191);
MVP		0.98
MPC		1.4
ClinPred		0.92	D
GERP RS		5.2
Varity_R		0.51
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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-110366348;