Genetic Variant NM_005884.5:c.98C>T (chr19-39169651-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_005884.5(PAK4):c.98C>T(p.Thr33Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000167 in 1,612,528 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

PAK4
NM_005884.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.66

Publications

1 publications found

Variant links:

Genes affected

PAK4 (HGNC:16059): (p21 (RAC1) activated kinase 4) PAK proteins, a family of serine/threonine p21-activating kinases, include PAK1, PAK2, PAK3 and PAK4. PAK proteins are critical effectors that link Rho GTPases to cytoskeleton reorganization and nuclear signaling. They serve as targets for the small GTP binding proteins Cdc42 and Rac and have been implicated in a wide range of biological activities. PAK4 interacts specifically with the GTP-bound form of Cdc42Hs and weakly activates the JNK family of MAP kinases. PAK4 is a mediator of filopodia formation and may play a role in the reorganization of the actin cytoskeleton. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

PAK4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 10 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005884.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PAK4	NM_005884.5	MANE Select	c.98C>T	p.Thr33Met	missense	Exon 3 of 10	NP_005875.1	O96013-1
PAK4	NM_001014831.3		c.98C>T	p.Thr33Met	missense	Exon 4 of 11	NP_001014831.1	O96013-1
PAK4	NM_001014832.2		c.98C>T	p.Thr33Met	missense	Exon 2 of 9	NP_001014832.1	O96013-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PAK4	ENST00000360442.8	TSL:5 MANE Select	c.98C>T	p.Thr33Met	missense	Exon 3 of 10	ENSP00000353625.3	O96013-1
PAK4	ENST00000358301.7	TSL:1	c.98C>T	p.Thr33Met	missense	Exon 2 of 9	ENSP00000351049.2	O96013-1
PAK4	ENST00000593690.5	TSL:1	c.98C>T	p.Thr33Met	missense	Exon 4 of 11	ENSP00000469413.1	O96013-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000448

AC:

AN:

245394

AF XY:

0.0000598

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000329

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000455

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1460408

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726538

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52492

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5558

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1111836

Other (OTH)

AF:

0.0000166

AC:

AN:

60334

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

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:

0.0000657

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41442

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000580

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

67990

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000540

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000660

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.79

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.51

MetaRNN

Uncertain

0.54

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

3.0

PhyloP100

3.7

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.55

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.014

Polyphen

0.98

Vest4

0.55

MutPred

0.54

Loss of phosphorylation at T33 (P = 0.0376)

MVP

0.78

MPC

0.86

ClinPred

0.53

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.67

Mutation Taster

=64/36

polymorphism

(source)

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

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