rs373324891

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005884.5(PAK4):​c.196G>A​(p.Ala66Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,447,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A66S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PAK4
NM_005884.5 missense

Scores

2
17

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.523
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.16970316).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PAK4NM_005884.5 linkc.196G>A p.Ala66Thr 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.196G>A p.Ala66Thr missense_variant Exon 3 of 10 5 NM_005884.5 ENSP00000353625.3 O96013-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000423
AC:
1
AN:
236396
Hom.:
0
AF XY:
0.00000770
AC XY:
1
AN XY:
129848
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:
0.00000945
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000207
AC:
3
AN:
1447248
Hom.:
0
Cov.:
33
AF XY:
0.00000139
AC XY:
1
AN XY:
718214
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000181
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.066
BayesDel_addAF
Benign
-0.030
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
20
DANN
Uncertain
0.98
DEOGEN2
Benign
0.092
.;.;.;T;T;T;.;.;T
Eigen
Benign
-0.18
Eigen_PC
Benign
-0.16
FATHMM_MKL
Benign
0.56
D
LIST_S2
Benign
0.81
T;.;D;D;.;.;T;T;D
M_CAP
Benign
0.037
D
MetaRNN
Benign
0.17
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.0
.;N;N;.;N;N;N;.;N
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
-0.52
.;.;N;.;N;.;.;.;N
REVEL
Benign
0.099
Sift
Benign
0.60
.;.;T;.;D;.;.;.;D
Sift4G
Benign
0.29
T;T;T;T;T;T;T;T;T
Polyphen
0.73, 0.47, 0.87
.;P;P;.;P;P;P;.;P
Vest4
0.36, 0.44, 0.41, 0.46, 0.30, 0.39
MutPred
0.31
.;Gain of phosphorylation at A66 (P = 0.0447);Gain of phosphorylation at A66 (P = 0.0447);Gain of phosphorylation at A66 (P = 0.0447);Gain of phosphorylation at A66 (P = 0.0447);Gain of phosphorylation at A66 (P = 0.0447);Gain of phosphorylation at A66 (P = 0.0447);Gain of phosphorylation at A66 (P = 0.0447);Gain of phosphorylation at A66 (P = 0.0447);
MVP
0.61
MPC
0.69
ClinPred
0.42
T
GERP RS
3.8
Varity_R
0.044
gMVP
0.41

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: rs373324891; hg19: chr19-39660389; API