X-111123113-G-C

Position:

• chrX-111123113-G-C

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.10G>C​(p.Gly4Arg) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G4S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: PAK3 NM_002578.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.938

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=0.21888512).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAK3	NM_002578.5	c.10G>C	p.Gly4Arg	missense_variant	5/18	ENST00000372007.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAK3	ENST00000372007.10	c.10G>C	p.Gly4Arg	missense_variant	5/18	1	NM_002578.5	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000727 Hom.: 8

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	.;.;T;.;.;.;T;.;.;T;T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	.;D;.;.;.;.;D;D;D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.1	L;L;L;L;L;L;.;L;L;L;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.17
Sift	Uncertain	0.011	D;D;D;D;D;D;D;D;D;D;.
Sift4G	Benign	0.23	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.16	B;B;B;B;B;B;.;B;B;B;.
Vest4		0.32
MutPred		0.20		Gain of solvent accessibility (P = 0.0674);Gain of solvent accessibility (P = 0.0674);Gain of solvent accessibility (P = 0.0674);Gain of solvent accessibility (P = 0.0674);Gain of solvent accessibility (P = 0.0674);Gain of solvent accessibility (P = 0.0674);Gain of solvent accessibility (P = 0.0674);Gain of solvent accessibility (P = 0.0674);Gain of solvent accessibility (P = 0.0674);Gain of solvent accessibility (P = 0.0674);Gain of solvent accessibility (P = 0.0674);
MVP		0.63
MPC		1.7
ClinPred		0.43	T
GERP RS		-3.1
Varity_R		0.16
gMVP		0.31

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

LitVar

Other links and lift over

dbSNP: rs140296303; hg19: chrX-110366341;