STRADA

protein-coding

STE20 related adaptor alpha

Gene summary

The protein encoded by this gene contains a STE20-like kinase domain, but lacks several residues that are critical for catalytic activity, so it is termed a 'pseudokinase'. The protein forms a heterotrimeric complex with serine/threonine kinase 11 (STK11, also known as LKB1) and the scaffolding protein calcium binding protein 39 (CAB39, also known as MO25). The protein activates STK11 leading to the phosphorylation of both proteins and excluding STK11 from the nucleus. The protein is necessary for STK11-induced G1 cell cycle arrest. A mutation in this gene has been shown to result in polyhydramnios, megalencephaly, and symptomatic epilepsy (PMSE) syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. Additional transcript variants have been described but their full-length nature is not known. [provided by RefSeq, Sep 2009]

MANE transcript

NM_001003787.4

Inheritance

ClinVar variants

P:25U:183B:112

Top phenotype

Polyhydramnios, megalencephaly, and symptomatic epilepsy

gnomAD constraint

pLI —, LoF o/e 0.5

Max pathogenic AF

—

Genomic locus

chr17:63,682,336-63,741,986

External References & Databases

Ensembl (ENSG00000266173)

Transcript & Mutation Effects

hg38 • Region Span ~59.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

polyhydramnios, megalencephaly, and symptomatic epilepsyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012611

Submitter: G2P

polyhydramnios, megalencephaly, and symptomatic epilepsySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012611

Submitter: Labcorp Genetics (formerly Invitae)

polyhydramnios, megalencephaly, and symptomatic epilepsySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012611

Submitter: Genomics England PanelApp

polyhydramnios, megalencephaly, and symptomatic epilepsySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012611

Submitter: PanelApp Australia

polyhydramnios, megalencephaly, and symptomatic epilepsySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012611

Submitter: Orphanet

Clinical Genomic Database (CGD)

Polyhydramnios, megalencephaly, and symptomatic epilepsyAR

Manifestation: Cardiovascular; Endocrine; Neurologic; Obstetric; Renal

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Comments: The condition can affect the pregnancy (due to polyhydramnios) with the affected individual

Refs: 17522105

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to STRADA variants in ClinVar

9 Conditions Cataloged

Polyhydramnios, megalencephaly, and symptomatic epilepsyTotal: 401

Inborn genetic diseasesTotal: 46

not providedTotal: 41

not specifiedTotal: 18

STRADA-related disorderTotal: 13

Self-limited epilepsy with centrotemporal spikesTotal: 3

intellectual deficiencyTotal: 1

EpilepsyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001003787.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	106 clinvar		108
missense	2 clinvar		172 clinvar	6 clinvar		180
nonsense	6 clinvar	1 clinvar	2 clinvar			9
start loss						0
frameshift	9 clinvar		5 clinvar			14
splice donor/acceptor (+/-2bp)	1 clinvar	6 clinvar	2 clinvar			9
Total	18	7	183	112	0	320

Highest pathogenic variant AF is 0.00011282483

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 100 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001003787.4	RefSeq	NP_001003787.1	12	MANE Select
ENST00000336174.12	Ensembl	ENSP00000336655.6	12	MANE Select
NM_001003786.3	RefSeq	NP_001003786.1	10	Standard
NM_001003788.3	RefSeq	NP_001003788.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

mTOR signaling pathway - Homo sapiens (human)
AMPK signaling pathway - Homo sapiens (human)
AMP-activated Protein Kinase (AMPK) Signaling
Focal Adhesion-PI3K-Akt-mTOR-signaling pathway
Signal Transduction

Biological Process

MAPK cascade
protein phosphorylation
protein export from nucleus
cell cycle arrest
signal transduction by protein phosphorylation

Molecular Function

protein kinase activity
protein serine/threonine kinase activity
protein binding
ATP binding
kinase binding

Cellular Component

nucleus
nucleoplasm
cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000336174
Coding exons: 12
Length: 39139
Individuals with no LoFs: 125704
Homozygous LoFs: 0
Heterozygous LoFs: 44
Defined: 125748
p: 0.000175

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.49	190	257	0.739	0.0000145	2830
Missense (PolyPhen)		70	102.45	0.68323		1150
Synonymous	0.509	96	103	0.936	0.00000615	844
Loss of Function	2.36	13	26.0	0.501	0.00000151	264

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000062	rare
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00038	0.00038	rare
Finnish	0.00033	0.00032	rare
European (Non-Finnish)	0.00019	0.00019	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Pseudokinase which, in complex with CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta), binds to and activates STK11/LKB1. Adopts a closed conformation typical of active protein kinases and binds STK11/LKB1 as a pseudosubstrate, promoting conformational change of STK11/LKB1 in an active conformation. {ECO:0000269|PubMed:12805220, ECO:0000269|PubMed:14517248, ECO:0000269|PubMed:19892943}.;
Disease: DISEASE: Note=A homozygous 7-kb deletion involving STRADA is a cause of a syndrome characterized by polyhydramnios, megalencephaly and symptomatic epilepsy.;

Recessive Scores

pRec: 0.132

Intolerance Scores

LoFtool: 0.801
RVIS EVS: 0.06
RVIS percentile EVS: 58.74

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.775

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium