TRIO

protein-coding

trio Rho guanine nucleotide exchange factor, the group of I-set domain containing|Dbl family Rho GEFs

Gene summary

This gene encodes a large protein that functions as a GDP to GTP exchange factor. This protein promotes the reorganization of the actin cytoskeleton, thereby playing a role in cell migration and growth. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

MANE transcript

NM_007118.4

Inheritance

ClinVar variants

P:206U:1087B:420

Top phenotype

Intellectual developmental disorder, autosomal dominant 44, with microcephaly; Intellectual developmental disorder, autosomal dominant 63, with macrocephaly

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chr5:14,143,342-14,532,128

External References & Databases

Ensembl (ENSG00000038382)

Transcript & Mutation Effects

hg38 • Region Span ~388.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, autosomal dominant 63, with macrocephalySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032939

Submitter: G2P

intellectual developmental disorder, autosomal dominant 63, with macrocephalySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032939

Submitter: PanelApp Australia

intellectual developmental disorder, autosomal dominant 44, with microcephalySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014892

Submitter: PanelApp Australia

intellectual developmental disorder, autosomal dominant 44, with microcephalySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014892

Submitter: Orphanet

intellectual developmental disorder, autosomal dominant 44, with microcephalySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014892

Submitter: Ambry Genetics

intellectual developmental disorder, autosomal dominant 63, with macrocephalyMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032939

Submitter: Ambry Genetics

syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: Illumina

syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: ClinGen

TRIO encodes a Rho guanine nucleotide exchange factor (RhoGEF) that plays essential roles in neuronal development. Variants in TRIO were first reported in relation to autosomal dominant syndromic intellectual disability (ID) in 2016 (Ba et al., PMID: 26721934). Numerous variants in TRIO, including nonsense, frameshift and missense variants, have been reported, with most variants occurring de novo. Pathogenic variants in TRIO are associated with neurodevelopmental disorders, including ID and autism spectrum disorder. Other features include gastrointestinal problems, facial and skeletal dysmorphism. Missense variants cluster in two domains, the spectrin repeat and the RAC1-activating GEFD1. Individuals with variants in the spectrin domain have severe ID associated with macrocephaly and recognizable facial dysmorphism, whereas individuals with GEFD1 variants display milder ID and microcephaly (PMID: 32109419). Functional studies show that spectrin variants result in hyper-activation of RAC1, while GEFD1 variants cause hypo-activation of RAC1. RAC1 activation levels are correlated with the head size of affected individuals. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 25 probands in 3 publications (PMIDs: 26721934, 27418539, 32109419). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease association is also supported by TRIO’s role in neurogenesis, migration and synapse formation; protein interaction between TRIO and proteins involved in ID (RAC1, FLNA), functional alterations in non-patient cells, and mouse and xenopus models (4 points). In summary, TRIO is definitely associated with syndromic intellectual disability. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 11/03/2021 (SOP Version 8).

intellectual developmental disorder, autosomal dominant 44, with microcephalySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014892

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 44, with microcephaly; Intellectual developmental disorder, autosomal dominant 63, with macrocephalyAD

Manifestation: Craniofacial; Dental; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 18388777; 26721934; 27418539; 32109419

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TRIO variants in ClinVar

28 Conditions Cataloged

not providedTotal: 1258

Inborn genetic diseasesTotal: 442

not specifiedTotal: 246

Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndromeTotal: 217

TRIO-related disorderTotal: 208

Intellectual developmental disorder, autosomal dominant 63, with macrocephalyTotal: 93

Intellectual disabilityTotal: 14

See casesTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007118.4. 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		1 clinvar	18 clinvar	271 clinvar	6 clinvar	296
missense	9 clinvar	31 clinvar	1036 clinvar	137 clinvar	6 clinvar	1219
nonsense	28 clinvar	28 clinvar	7 clinvar			63
start loss			1 clinvar			1
frameshift	37 clinvar	49 clinvar	9 clinvar			95
splice donor/acceptor (+/-2bp)	8 clinvar	15 clinvar	16 clinvar			39
Total	82	124	1087	408	12	1713

Highest pathogenic variant AF is 0.00008417459

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 20 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_007118.4	RefSeq	NP_009049.2	57	MANE Select
ENST00000344204.9	Ensembl	ENSP00000339299.4	57	MANE Select
ENST00000509967.6	Ensembl	ENSP00000445592.1	30	Standard
ENST00000512070.6	Ensembl	ENSP00000421555.2	48	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Regulation of Microtubule Cytoskeleton
Developmental Biology
Signaling by GPCR
Signal Transduction
pkc-catalyzed phosphorylation of inhibitory phosphoprotein of myosin phosphatase

Biological Process

protein phosphorylation
transmembrane receptor protein tyrosine phosphatase signaling pathway
G protein-coupled receptor signaling pathway
regulation of Rho protein signal transduction
positive regulation of apoptotic process

Molecular Function

protein serine/threonine kinase activity
guanyl-nucleotide exchange factor activity
Rho guanyl-nucleotide exchange factor activity
protein binding
ATP binding

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000344204
Coding exons: 57
Length: 388425
Individuals with no LoFs: 125719
Homozygous LoFs: 0
Heterozygous LoFs: 29
Defined: 125748
p: 0.000115

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	5.32	1143	1.77e+3	0.645	0.000112	20390
Missense (PolyPhen)		207	470.43	0.44002		5502
Synonymous	-0.925	769	737	1.04	0.0000520	5904
Loss of Function	10.6	14	158	0.0887	0.00000864	1773

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00027	0.00027	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00016	0.00015	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Guanine nucleotide exchange factor (GEF) for RHOA and RAC1 GTPases (PubMed:8643598, PubMed:27418539). Involved in coordinating actin remodeling, which is necessary for cell migration and growth (PubMed:10341202). In developing hippocampal neurons, limits dendrite formation, without affecting the establishment of axon polarity. Once dendrites are formed, involved in the control of synaptic function by regulating the endocytosis of AMPA-selective glutamate receptors (AMPARs) at CA1 excitatory synapses (By similarity). May act as a regulator of adipogenesis (By similarity). {ECO:0000250|UniProtKB:F1M0Z1, ECO:0000269|PubMed:10341202, ECO:0000269|PubMed:27418539, ECO:0000269|PubMed:8643598}.;
Disease: DISEASE: Mental retardation, autosomal dominant 44 (MRD44) [MIM:617061]: A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD44 patients manifest developmental delay, variable intellectual disability, distinctive facial features, and abnormalities of the fingers. Most patients also have microcephaly. {ECO:0000269|PubMed:26721934, ECO:0000269|PubMed:27418539}. Note=The disease may be caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.254
RVIS EVS: -4.04
RVIS percentile EVS: 0.18

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.892

Gene Damage Prediction

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