chrX-111142119-C-T

Variant names:

• chrX-111142119-C-T
• rs121434612
• NM_002578.5:c.199C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_002578.5(PAK3):​c.199C>T​(p.Arg67Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: PAK3 NM_002578.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.57
• Publications: 18 publications found

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]

PAK3 Gene-Disease associations (from GenCC):

• corpus callosum, agenesis of

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• intellectual disability, X-linked 30

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817
• PP5: Variant X-111142119-C-T is Pathogenic according to our data. Variant chrX-111142119-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 11569.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAK3	NM_002578.5	c.199C>T	p.Arg67Cys	missense_variant	Exon 6 of 18	ENST00000372007.10	NP_002569.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAK3	ENST00000372007.10	c.199C>T	p.Arg67Cys	missense_variant	Exon 6 of 18	1	NM_002578.5	ENSP00000361077.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1074691 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 343645

African (AFR) AF: 0.00 AC: 0 AN: 25956

American (AMR) AF: 0.00 AC: 0 AN: 35162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19205

East Asian (EAS) AF: 0.00 AC: 0 AN: 30118

South Asian (SAS) AF: 0.00 AC: 0 AN: 53588

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40507

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4070

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 820771

Other (OTH) AF: 0.00 AC: 0 AN: 45314

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jan 20, 2025

GeneDx

Significance: Pathogenic

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; This variant is associated with the following publications: (PMID: 23622267, 9332663, 24556213, 10946356, 17537723, 31943058, 26350204) -

Intellectual disability, X-linked 30 Pathogenic:1

Aug 14, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	.;.;T;.;.;.;T;.;.;T;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;.;.;.;.;D;D;D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.8	M;M;M;M;M;M;.;M;M;M;.
PhyloP100		7.6
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.5	D;D;D;D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;.;D;D;D;.
Vest4		0.60
MutPred		0.43		Loss of glycosylation at P68 (P = 0.0449);Loss of glycosylation at P68 (P = 0.0449);Loss of glycosylation at P68 (P = 0.0449);Loss of glycosylation at P68 (P = 0.0449);Loss of glycosylation at P68 (P = 0.0449);Loss of glycosylation at P68 (P = 0.0449);Loss of glycosylation at P68 (P = 0.0449);Loss of glycosylation at P68 (P = 0.0449);Loss of glycosylation at P68 (P = 0.0449);Loss of glycosylation at P68 (P = 0.0449);.;
MVP		0.96
MPC		2.4
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.89
gMVP		0.73
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121434612; hg19: chrX-110385347; COSMIC: COSV107297491; COSMIC: COSV107297491;