11-77336139-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2

The NM_002576.5(PAK1):​c.1360G>A​(p.Ala454Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

PAK1
NM_002576.5 missense

Scores

5
9
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57
Variant links:
Genes affected
PAK1 (HGNC:8590): (p21 (RAC1) activated kinase 1) This gene encodes a family member of serine/threonine p21-activating kinases, known as PAK proteins. These proteins are critical effectors that link RhoGTPases to cytoskeleton reorganization and nuclear signaling, and they serve as targets for the small GTP binding proteins Cdc42 and Rac. This specific family member regulates cell motility and morphology. Mutations in this gene have been associated with macrocephaly, seizures, and speech delay. Overexpression of this gene is also reported in many cancer types, and particularly in breast cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2020]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1
In a domain Protein kinase (size 251) in uniprot entity PAK1_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in NM_002576.5
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the PAK1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 21 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 4.0036 (above the threshold of 3.09). Trascript score misZ: 3.8133 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual developmental disorder with macrocephaly, seizures, and speech delay.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PAK1NM_002576.5 linkc.1360G>A p.Ala454Thr missense_variant Exon 13 of 15 ENST00000356341.8 NP_002567.3 Q13153-1A0A024R5P0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PAK1ENST00000356341.8 linkc.1360G>A p.Ala454Thr missense_variant Exon 13 of 15 1 NM_002576.5 ENSP00000348696.4 Q13153-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Jul 11, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.86
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.020
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.27
T;T;.;T
Eigen
Uncertain
0.46
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D;D;D;D
M_CAP
Benign
0.022
T
MetaRNN
Uncertain
0.74
D;D;D;D
MetaSVM
Benign
-0.67
T
MutationAssessor
Benign
0.61
N;.;N;.
PrimateAI
Pathogenic
0.91
D
PROVEAN
Uncertain
-3.8
D;D;D;D
REVEL
Uncertain
0.54
Sift
Uncertain
0.0040
D;D;D;T
Sift4G
Uncertain
0.017
D;D;D;D
Polyphen
0.99
D;D;D;D
Vest4
0.77
MutPred
0.45
Gain of disorder (P = 0.2724);Gain of disorder (P = 0.2724);Gain of disorder (P = 0.2724);.;
MVP
0.78
MPC
2.4
ClinPred
0.97
D
GERP RS
5.9
Varity_R
0.75
gMVP
0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-77047184; API