rs121434612

chrX-111142119-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2 PP3 PP5

The NM_002578.5(PAK3):c.199C>T(p.Arg67Cys) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• 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 no assertion criteria provided P:1
• Conservation: PhyloP100: 7.57

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 3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PAK3
• 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 id is 11569.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-111142119-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAK3	NM_002578.5	c.199C>T	p.Arg67Cys	missense_variant	6/18	ENST00000372007.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAK3	ENST00000372007.10	c.199C>T	p.Arg67Cys	missense_variant	6/18	1	NM_002578.5	P1

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

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability, X-linked 30 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 14, 2000

- -

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
FATHMM_MKL	Pathogenic	0.98	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;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A
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

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: rs121434612; hg19: chrX-110385347;