Variant X-111142119-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3PP5

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. 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

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.57

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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.

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	Protein	UniProt
PAK3	NM_002578.5 linkuse as main transcript	c.199C>T	p.Arg67Cys	missense_variant	6/18	ENST00000372007.10	NP_002569.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAK3	ENST00000372007.10 linkuse as main transcript	c.199C>T	p.Arg67Cys	missense_variant	6/18	1	NM_002578.5	ENSP00000361077	P1	O75914-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1074691

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

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

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.46

.;.;T;.;.;.;T;.;.;T;T

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

.;D;.;.;.;.;D;D;D;D;D

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.82

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.31

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

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over