TRIO

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

Basic information

Region (hg38): 5:14143341-14532128

Links

ENSG00000038382 ∙ NCBI:7204 ∙ OMIM:601893 ∙ HGNC:12303 ∙ Uniprot:O75962 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• intellectual disability, autosomal dominant 40 (Strong), mode of inheritance: AD
• micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome (Strong), mode of inheritance: AD
• intellectual developmental disorder, autosomal dominant 63, with macrocephaly (Moderate), mode of inheritance: AD
• micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome (Supportive), mode of inheritance: AD
• syndromic intellectual disability (Definitive), mode of inheritance: AD
• micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome (Strong), mode of inheritance: AD
• syndromic intellectual disability (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Intellectual developmental disorder, autosomal dominant 44, with microcephaly; Intellectual developmental disorder, autosomal dominant 63, with macrocephaly	AD	General	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	Craniofacial; Dental; Musculoskeletal; Neurologic	18388777; 26721934; 27418539; 32109419

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TRIO gene.

• not provided (908 variants)
• Inborn genetic diseases (139 variants)
• Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome (104 variants)
• Intellectual developmental disorder, autosomal dominant 63, with macrocephaly (38 variants)
• not specified (33 variants)
• TRIO-related condition (31 variants)
• Intellectual disability (9 variants)
• Intellectual developmental disorder, autosomal dominant 63, with macrocephaly;Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome (8 variants)
• See cases (7 variants)
• Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome;Intellectual developmental disorder, autosomal dominant 63, with macrocephaly (6 variants)
• Autosomal recessive nonsyndromic hearing loss 28 (2 variants)
• TRIO-Related Disorders (2 variants)
• Neurodevelopmental disorder (2 variants)
• Autism spectrum disorder (2 variants)
• Tip-toe gait (1 variants)
• Developmental disorder (1 variants)
• Autism;Intellectual disability (1 variants)
• Neurodevelopmental delay (1 variants)
• Developmental delay (1 variants)
• Seizure (1 variants)
• TRIO-Related Disorder (1 variants)
• Intellectual disability, autosomal dominant 40 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TRIO gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			6	133	18	157
missense	11	16	470	54	11	562
nonsense	17	12	2			31
start loss						0
frameshift	12	20	5			37
inframe indel			17	8		25
splice donor/acceptor (+/-2bp)	1	6	1			8
splice region		2	25	23	5	55
non coding			5	105	153	263
Total	41	54	506	300	182

Highest pathogenic variant AF is 0.00000658

Variants in TRIO

This is a list of pathogenic ClinVar variants found in the TRIO region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
5-14143705-G-A			Likely benign (Oct 02, 2018)
5-14143721-C-T			Likely benign (Dec 01, 2023)
5-14143738-A-G		Inborn genetic diseases	Uncertain significance (Apr 18, 2023)
5-14143747-G-A		Inborn genetic diseases	Uncertain significance (Nov 21, 2023)
5-14143746-A-AGCC			Uncertain significance (May 31, 2023)
5-14143748-C-G		Inborn genetic diseases	Uncertain significance (Nov 21, 2023)
5-14143754-CCCCCGCCGCGTCCTCCGG-C		Inborn genetic diseases	Uncertain significance (Nov 20, 2023)
5-14143758-C-T			Likely benign (Oct 01, 2022)
5-14143759-G-A		Inborn genetic diseases • TRIO-related disorder	Benign/Likely benign (Feb 16, 2024)
5-14143759-G-T		Developmental delay	Uncertain significance (-)
5-14143766-C-T		Inborn genetic diseases • TRIO-related disorder	Conflicting classifications of pathogenicity (Jul 01, 2023)
5-14143769-C-T		Inborn genetic diseases	Conflicting classifications of pathogenicity (Oct 01, 2021)
5-14143773-C-A			Likely benign (Aug 03, 2018)
5-14143778-C-G		Intellectual developmental disorder, autosomal dominant 63, with macrocephaly;Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome	Uncertain significance (Feb 26, 2021)
5-14143778-C-CCGCGGCGGCCAG			Uncertain significance (Sep 25, 2022)
5-14143780-GC-TT			Uncertain significance (Apr 25, 2023)
5-14143783-G-A		Inborn genetic diseases	Uncertain significance (Apr 07, 2023)
5-14143784-C-T			Uncertain significance (Feb 11, 2022)
5-14143792-G-A		TRIO-related disorder • Inborn genetic diseases	Benign/Likely benign (Jan 16, 2024)
5-14143802-C-A			Pathogenic (Apr 19, 2023)
5-14143805-G-T		Intellectual developmental disorder, autosomal dominant 63, with macrocephaly	Uncertain significance (Jun 11, 2019)
5-14143815-C-T			Likely benign (Apr 23, 2018)
5-14143827-G-C		Inborn genetic diseases	Uncertain significance (Jul 25, 2023)
5-14143831-G-A		Inborn genetic diseases	Uncertain significance (Oct 18, 2021)
5-14143845-C-T			Likely benign (Sep 01, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TRIO	protein_coding	protein_coding	ENST00000344204	57	388425

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	4.46e-16	125719	0	29	125748	0.000115

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	5.32	1143	1.77e+3	0.645	0.000112	20390
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000212	0.000210
Ashkenazi Jewish	0.00	0.00
East Asian	0.000272	0.000272
Finnish	0.0000925	0.0000924
European (Non-Finnish)	0.000162	0.000149
Middle Eastern	0.000272	0.000272
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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.
• Pathway: Regulation of Microtubule Cytoskeleton;Developmental Biology;Signaling by GPCR;Signal Transduction;pkc-catalyzed phosphorylation of inhibitory phosphoprotein of myosin phosphatase;rho cell motility signaling pathway;rac1 cell motility signaling pathway;Rho GTPase cycle;Signaling by Rho GTPases;DCC mediated attractive signaling;Regulation of RAC1 activity;NRAGE signals death through JNK;Netrin-1 signaling;Death Receptor Signalling;p75 NTR receptor-mediated signalling;Axon guidance;G alpha (12/13) signalling events;G alpha (q) signalling events;GPCR downstream signalling;Netrin-mediated signaling events;Cell death signalling via NRAGE, NRIF and NADE;Regulation of RhoA activity (Consensus)

Intolerance Scores

• loftool: 0.254
• rvis_EVS: -4.04
• rvis_percentile_EVS: 0.18

Haploinsufficiency Scores

• pHI: 0.756
• hipred: Y
• hipred_score: 0.756
• ghis: 0.641

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: H
• gene_indispensability_pred: E
• gene_indispensability_score: 0.892

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Trio
• Phenotype: muscle phenotype; cellular phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); growth/size/body region phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Gene ontology

• 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;negative regulation of fat cell differentiation;regulation of small GTPase mediated signal transduction
• Cellular component: cytosol
• Molecular function: protein serine/threonine kinase activity;guanyl-nucleotide exchange factor activity;Rho guanyl-nucleotide exchange factor activity;protein binding;ATP binding