19-39173643-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_005884.5(PAK4):c.731C>T(p.Ser244Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000916 in 1,419,436 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: not found (cov: 32)
Exomes 𝑓: 0.0000092 ( 0 hom. )
Consequence
PAK4
NM_005884.5 missense
NM_005884.5 missense
Scores
1
3
10
Clinical Significance
Conservation
PhyloP100: 0.885
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=0.20165852).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAK4 | NM_005884.5 | c.731C>T | p.Ser244Phe | missense_variant | 5/10 | ENST00000360442.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAK4 | ENST00000360442.8 | c.731C>T | p.Ser244Phe | missense_variant | 5/10 | 5 | NM_005884.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.0000144 AC: 3AN: 208292Hom.: 0 AF XY: 0.0000175 AC XY: 2AN XY: 114166
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GnomAD4 exome AF: 0.00000916 AC: 13AN: 1419436Hom.: 0 Cov.: 34 AF XY: 0.0000157 AC XY: 11AN XY: 701428
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ExAC
?
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3
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 | Feb 10, 2022 | The c.731C>T (p.S244F) alteration is located in exon 6 (coding exon 3) of the PAK4 gene. This alteration results from a C to T substitution at nucleotide position 731, causing the serine (S) at amino acid position 244 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;.;T;.;.;T;T;T
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
Sift4G
Uncertain
D;D;D;D;D;D;D;D
Polyphen
0.16, 1.0, 0.28
.;B;D;B;B;B;.;B
Vest4
0.38, 0.39, 0.34, 0.36, 0.39, 0.33
MutPred
0.30
.;.;.;Loss of phosphorylation at S244 (P = 0.0137);Loss of phosphorylation at S244 (P = 0.0137);.;.;Loss of phosphorylation at S244 (P = 0.0137);
MVP
MPC
0.26
ClinPred
T
GERP RS
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