11-77336090-A-C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_002576.5(PAK1):c.1409T>G(p.Leu470Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L470Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAK1 NM_002576.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.95

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a helix (size 10) in uniprot entity PAK1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_002576.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-77336090-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2442056.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, PAK1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93
• PP5: Variant 11-77336090-A-C is Pathogenic according to our data. Variant chr11-77336090-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 982892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAK1	NM_002576.5	c.1409T>G	p.Leu470Arg	missense_variant	13/15	ENST00000356341.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAK1	ENST00000356341.8	c.1409T>G	p.Leu470Arg	missense_variant	13/15	1	NM_002576.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual developmental disorder with macrocephaly, seizures, and speech delay Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 23, 2023	Criteria applied: PS2_MOD,PM1,PM5,PS4_SUP,PM2_SUP,PP3; Re-Eval 23.11.2023 RoJ -
Likely pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jul 09, 2021	This PAK1 variant is absent from a large population dataset and has not been reported in the literature, to our knowledge. It has an entry in ClinVar. Three bioinformatics tools queried predict that this substitution would be damaging, and the leucine residue at this position is conserved across all vertebrate species assessed. This leucine to arginine substitution is located in PAK1 kinase domain. The crystal structure of the human PAK1 protein shows this residue (Leu470) interacts with the inhibitory switch (IS) domain, which is required for autoinhibition of PAK1 kinase activity. This variant is not predicted to affect normal exon 13 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.1409T>G to be likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T;.;T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.7	L;.;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.7	D;D;D;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.97
MutPred		0.82		Gain of methylation at L470 (P = 0.0248);Gain of methylation at L470 (P = 0.0248);Gain of methylation at L470 (P = 0.0248);.;
MVP		0.92
MPC		3.0
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.95
gMVP		0.97

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

Other links and lift over

dbSNP: rs1942648391; hg19: chr11-77047135;