TRIO

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

Basic information

Region (hg38): 5:14143342-14532128

Links

ENSG00000038382

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

Phenotypes

GenCC

Source: genCC

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
intellectual developmental disorder, autosomal dominant 63, with macrocephaly (Strong), 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 (1067 variants)
Inborn_genetic_diseases (366 variants)
Micrognathia-recurrent_infections-behavioral_abnormalities-mild_intellectual_disability_syndrome (188 variants)
TRIO-related_disorder (146 variants)
not_specified (81 variants)
Intellectual_developmental_disorder,_autosomal_dominant_63,_with_macrocephaly (74 variants)
Intellectual_disability (14 variants)
See_cases (7 variants)
Autosomal_recessive_nonsyndromic_hearing_loss_28 (3 variants)
Tip-toe_gait (3 variants)
Neurodevelopmental_disorder (2 variants)
Autism_spectrum_disorder (2 variants)
Developmental_delay (2 variants)
EBV-positive_nodal_T-_and_NK-cell_lymphoma (2 variants)
Deafness (1 variants)
Intellectual_disability,_autosomal_dominant_40 (1 variants)
Syndromic_intellectual_disability (1 variants)
Neurodevelopmental_delay (1 variants)
Microcephaly (1 variants)
Hereditary_ataxia (1 variants)
Congenital_anomaly_of_kidney_and_urinary_tract (1 variants)
Neurodevelopmental_abnormality (1 variants)
Developmental_disorder (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. These statistics are base on transcript: NM_000007118.4. Only rare variants are included in the table.

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.

Effect	PathogenicP	Likely pathogenicLP	VUSVUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	14 clinvar	194 clinvar	8 clinvar	217
missense	11 clinvar	28 clinvar	849 clinvar	112 clinvar	8 clinvar	1008
nonsense	25 clinvar	21 clinvar	5 clinvar			51
start loss						0
frameshift	25 clinvar	40 clinvar	7 clinvar			72
splice donor/acceptor (+/-2bp)	5 clinvar	11 clinvar	5 clinvar			21
Total	66	101	880	306	16

Highest pathogenic variant AF is 0.0000841746

Loading clinvar variants...

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