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GeneBe

19-39173042-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_005884.5(PAK4):c.329G>A(p.Arg110His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000135 in 1,548,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

PAK4
NM_005884.5 missense

Scores

1
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0620
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.124269426).
BS2
High AC in GnomAd at 16 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PAK4NM_005884.5 linkuse as main transcriptc.329G>A p.Arg110His missense_variant 4/10 ENST00000360442.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PAK4ENST00000360442.8 linkuse as main transcriptc.329G>A p.Arg110His missense_variant 4/105 NM_005884.5 P1O96013-1

Frequencies

GnomAD3 genomes
AF:
0.000105
AC:
16
AN:
152122
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00124
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000120
AC:
18
AN:
149598
Hom.:
0
AF XY:
0.000125
AC XY:
10
AN XY:
80060
show subpopulations
Gnomad AFR exome
AF:
0.000134
Gnomad AMR exome
AF:
0.0000813
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000185
Gnomad SAS exome
AF:
0.000264
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000125
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000140
AC:
195
AN:
1396730
Hom.:
0
Cov.:
33
AF XY:
0.000147
AC XY:
101
AN XY:
688944
show subpopulations
Gnomad4 AFR exome
AF:
0.0000951
Gnomad4 AMR exome
AF:
0.0000560
Gnomad4 ASJ exome
AF:
0.0000397
Gnomad4 EAS exome
AF:
0.000112
Gnomad4 SAS exome
AF:
0.000404
Gnomad4 FIN exome
AF:
0.0000208
Gnomad4 NFE exome
AF:
0.000139
Gnomad4 OTH exome
AF:
0.0000346
GnomAD4 genome
AF:
0.0000920
AC:
14
AN:
152240
Hom.:
0
Cov.:
32
AF XY:
0.0000941
AC XY:
7
AN XY:
74422
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000829
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000883
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000108
Hom.:
0
Bravo
AF:
0.0000642
ExAC
AF:
0.0000383
AC:
3
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 02, 2021The c.329G>A (p.R110H) alteration is located in exon 5 (coding exon 2) of the PAK4 gene. This alteration results from a G to A substitution at nucleotide position 329, causing the arginine (R) at amino acid position 110 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.45
Cadd
Benign
21
Dann
Uncertain
1.0
Eigen
Benign
-0.40
Eigen_PC
Benign
-0.37
FATHMM_MKL
Benign
0.24
N
LIST_S2
Benign
0.83
T;T;.;.;T
M_CAP
Benign
0.033
D
MetaRNN
Benign
0.12
T;T;T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
1.8
L;.;L;L;L
MutationTaster
Benign
1.0
D;N;N;N
PrimateAI
Benign
0.46
T
Sift4G
Benign
0.21
T;D;T;T;T
Polyphen
0.0030
B;.;B;B;B
Vest4
0.14
MVP
0.56
MPC
0.28
ClinPred
0.026
T
GERP RS
0.49
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.078
gMVP
0.24

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

LitVar

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

Other links and lift over

dbSNP: rs763084575; hg19: chr19-39663682; COSMIC: COSV100426531; COSMIC: COSV100426531; API