X-111123113-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_002578.5(PAK3):c.10G>A(p.Gly4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000176 in 1,201,151 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 76 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.00018 ( 0 hom. 73 hem. )

Consequence

PAK3
NM_002578.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.938

Publications

6 publications found

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 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
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

PAK3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0050827265).

BP6

Variant X-111123113-G-A is Benign according to our data. Variant chrX-111123113-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 436144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002578.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PAK3	NM_002578.5	MANE Select	c.10G>A	p.Gly4Ser	missense	Exon 5 of 18	NP_002569.1	O75914-2
PAK3	NM_001128168.3		c.10G>A	p.Gly4Ser	missense	Exon 5 of 20	NP_001121640.1	O75914-3
PAK3	NM_001128172.2		c.10G>A	p.Gly4Ser	missense	Exon 1 of 15	NP_001121644.1	O75914-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PAK3	ENST00000372007.10	TSL:1 MANE Select	c.10G>A	p.Gly4Ser	missense	Exon 5 of 18	ENSP00000361077.4	O75914-2
PAK3	ENST00000360648.8	TSL:1	c.10G>A	p.Gly4Ser	missense	Exon 1 of 16	ENSP00000353864.4	O75914-3
PAK3	ENST00000417227.5	TSL:1	c.10G>A	p.Gly4Ser	missense	Exon 1 of 15	ENSP00000389172.1	O75914-4

Frequencies

GnomAD3 genomes

AF:

0.000153

AC:

AN:

110940

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000955

Gnomad ASJ

AF:

0.00494

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000566

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000415

AC:

AN:

183118

AF XY:

0.000443

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000255

Gnomad ASJ exome

AF:

0.00829

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000490

Gnomad OTH exome

AF:

0.000663

GnomAD4 exome

AF:

0.000178

AC:

194

AN:

1090211

Hom.:

Cov.:

AF XY:

0.000205

AC XY:

AN XY:

356007

show subpopulations

African (AFR)

AF:

0.0000381

AC:

AN:

26257

American (AMR)

AF:

0.000227

AC:

AN:

35198

Ashkenazi Jewish (ASJ)

AF:

0.00694

AC:

134

AN:

19320

East Asian (EAS)

AF:

0.00

AC:

AN:

30177

South Asian (SAS)

AF:

0.0000185

AC:

AN:

53968

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4109

European-Non Finnish (NFE)

AF:

0.0000455

AC:

AN:

834791

Other (OTH)

AF:

0.000262

AC:

AN:

45861

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000153

AC:

AN:

110940

Hom.:

Cov.:

AF XY:

0.0000905

AC XY:

AN XY:

33166

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30423

American (AMR)

AF:

0.0000955

AC:

AN:

10472

Ashkenazi Jewish (ASJ)

AF:

0.00494

AC:

AN:

2634

East Asian (EAS)

AF:

0.00

AC:

AN:

3529

South Asian (SAS)

AF:

0.00

AC:

AN:

2599

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5907

Middle Eastern (MID)

AF:

0.00

AC:

AN:

234

European-Non Finnish (NFE)

AF:

0.0000566

AC:

AN:

52960

Other (OTH)

AF:

0.00

AC:

AN:

1499

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00102

Hom.:

Bravo

AF:

0.000185

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000272

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Inborn genetic diseases (1)

Intellectual disability, X-linked 30 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.76

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.069

FATHMM_MKL

Benign

0.074

LIST_S2

Uncertain

0.86

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.0051

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.55

PhyloP100

0.94

PrimateAI

Benign

0.40

PROVEAN

Benign

0.27

REVEL

Benign

0.19

Sift

Benign

0.64

Sift4G

Benign

0.73

Polyphen

0.0

Vest4

0.19

MVP

0.59

MPC

0.95

ClinPred

0.011

GERP RS

-3.1

PromoterAI

-0.031

Neutral

(source)

Varity_R

0.064

gMVP

0.15

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over