19-39169567-G-C
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_005884.5(PAK4):c.14G>C(p.Arg5Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
PAK4
NM_005884.5 missense
NM_005884.5 missense
Scores
1
5
8
Clinical Significance
Conservation
PhyloP100: 5.27
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 -2 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.22333789).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAK4 | NM_005884.5 | c.14G>C | p.Arg5Thr | missense_variant | 3/10 | ENST00000360442.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAK4 | ENST00000360442.8 | c.14G>C | p.Arg5Thr | missense_variant | 3/10 | 5 | NM_005884.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152102Hom.: 0 Cov.: 31
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00000400 AC: 1AN: 249982Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135272
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461070Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 726710
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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 submitter | clinical testing | Ambry Genetics | Aug 13, 2021 | The c.14G>C (p.R5T) alteration is located in exon 4 (coding exon 1) of the PAK4 gene. This alteration results from a G to C substitution at nucleotide position 14, causing the arginine (R) at amino acid position 5 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;D;T;.;.;D;T;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
N;N;N;N
PrimateAI
Uncertain
T
Sift4G
Uncertain
D;T;D;D;D;D;T;D;D
Polyphen
0.027, 0.22, 0.0040
.;B;B;.;B;B;B;.;B
Vest4
0.31, 0.24, 0.23, 0.26, 0.25, 0.26
MutPred
0.23
.;Gain of phosphorylation at R5 (P = 0.0387);Gain of phosphorylation at R5 (P = 0.0387);Gain of phosphorylation at R5 (P = 0.0387);Gain of phosphorylation at R5 (P = 0.0387);Gain of phosphorylation at R5 (P = 0.0387);Gain of phosphorylation at R5 (P = 0.0387);Gain of phosphorylation at R5 (P = 0.0387);Gain of phosphorylation at R5 (P = 0.0387);
MVP
MPC
0.35
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at