19-39169637-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_005884.5(PAK4):​c.84C>G​(p.His28Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,460 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 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

PAK4
NM_005884.5 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.03
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.024267823).
BS2
High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PAK4NM_005884.5 linkc.84C>G p.His28Gln missense_variant Exon 3 of 10 ENST00000360442.8 NP_005875.1 O96013-1A0A024R0J1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PAK4ENST00000360442.8 linkc.84C>G p.His28Gln missense_variant Exon 3 of 10 5 NM_005884.5 ENSP00000353625.3 O96013-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152134
Hom.:
0
Cov.:
31
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:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000804
AC:
2
AN:
248744
Hom.:
0
AF XY:
0.00000741
AC XY:
1
AN XY:
135004
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000179
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000684
AC:
10
AN:
1461326
Hom.:
0
Cov.:
33
AF XY:
0.00000963
AC XY:
7
AN XY:
726974
show subpopulations
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:
0.00000809
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152134
Hom.:
0
Cov.:
31
AF XY:
0.0000269
AC XY:
2
AN XY:
74290
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Sep 02, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.84C>G (p.H28Q) alteration is located in exon 4 (coding exon 1) of the PAK4 gene. This alteration results from a C to G substitution at nucleotide position 84, causing the histidine (H) at amino acid position 28 to be replaced by a glutamine (Q). 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
0.066
BayesDel_addAF
Benign
-0.065
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
0.0010
DANN
Benign
0.76
DEOGEN2
Benign
0.20
.;.;.;T;T;T;.;.;T
Eigen
Benign
-1.9
Eigen_PC
Benign
-1.8
FATHMM_MKL
Benign
0.028
N
LIST_S2
Benign
0.50
T;.;T;T;.;.;T;T;T
M_CAP
Uncertain
0.14
D
MetaRNN
Benign
0.024
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.73
T
MutationAssessor
Benign
-1.9
.;N;N;.;N;N;N;.;N
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
0.69
.;.;N;.;N;.;.;.;N
REVEL
Benign
0.28
Sift
Benign
0.62
.;.;T;.;T;.;.;.;T
Sift4G
Benign
0.67
T;T;T;T;T;T;T;T;T
Polyphen
0.0, 0.0050, 0.0010
.;B;B;.;B;B;B;.;B
Vest4
0.18, 0.18, 0.12, 0.22, 0.16, 0.18
MutPred
0.24
.;Loss of catalytic residue at H28 (P = 0.063);Loss of catalytic residue at H28 (P = 0.063);Loss of catalytic residue at H28 (P = 0.063);Loss of catalytic residue at H28 (P = 0.063);Loss of catalytic residue at H28 (P = 0.063);Loss of catalytic residue at H28 (P = 0.063);Loss of catalytic residue at H28 (P = 0.063);Loss of catalytic residue at H28 (P = 0.063);
MVP
0.57
MPC
0.35
ClinPred
0.023
T
GERP RS
-6.5
Varity_R
0.11
gMVP
0.40

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: rs75096376; hg19: chr19-39660277; API