GRIA3

glutamate ionotropic receptor AMPA type subunit 3, the group of Glutamate ionotropic receptor AMPA type subunits

Basic information

Region (hg38): X:123184152-123490915

Previous symbols: [ "GLUR3" ]

Links

ENSG00000125675 ∙ NCBI:2892 ∙ OMIM:305915 ∙ HGNC:4573 ∙ Uniprot:P42263 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• syndromic X-linked intellectual disability 94 (Definitive), mode of inheritance: XLR
• syndromic X-linked intellectual disability 94 (Limited), mode of inheritance: XL
• X-linked intellectual disability due to GRIA3 anomalies (Supportive), mode of inheritance: XL
• syndromic X-linked intellectual disability 94 (Definitive), mode of inheritance: XL
• syndromic X-linked intellectual disability 94 (Strong), mode of inheritance: XL
• X-linked complex neurodevelopmental disorder (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Intellectual developmental disorder, X-linked, syndromic, Wu type	XL	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	Musculoskeletal; Neurologic	17568425; 17989220; 19449417; 22124977

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GRIA3 gene.

• not provided (332 variants)
• Syndromic X-linked intellectual disability 94 (46 variants)
• Inborn genetic diseases (45 variants)
• not specified (16 variants)
• Intellectual disability (5 variants)
• GRIA3-related complex neurodevelopmental disorder (2 variants)
• GRIA3-related condition (2 variants)
• Epileptic encephalopathy (1 variants)
• Global developmental delay (1 variants)
• 7 conditions (1 variants)
• Neurodevelopmental abnormality (1 variants)
• Neurodevelopmental disorder (1 variants)
• Disrupted sleep-wake cycle with developmental delay and learning difficulty (1 variants)
• See cases (1 variants)
• Seizure (1 variants)
• History of neurodevelopmental disorder (1 variants)
• GRIA3-Related Disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GRIA3 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			4	79	10	93
missense	6	7	137	4	1	155
nonsense		3	1			4
start loss						0
frameshift	2	1	1		3	7
inframe indel		2	2			4
splice donor/acceptor (+/-2bp)			1			1
splice region			14	9	1	24
non coding				45	30	75
Total	8	13	146	128	44

Variants in GRIA3

This is a list of pathogenic ClinVar variants found in the GRIA3 region.

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

Position	Type	Phenotype	Significance	ClinVar
X-123184519-T-C			Benign (May 19, 2021)
X-123184533-A-AG		not specified • Syndromic X-linked intellectual disability 94 • Inborn genetic diseases	Benign (Aug 10, 2021)
X-123184537-T-C		Inborn genetic diseases	Conflicting classifications of pathogenicity (Jan 24, 2024)
X-123184545-C-A			Uncertain significance (Jun 20, 2021)
X-123184546-A-T			Likely benign (Aug 16, 2022)
X-123184549-A-C			Uncertain significance (Aug 15, 2022)
X-123184550-G-A		not specified • Inborn genetic diseases	Benign (Feb 01, 2024)
X-123184555-T-C		Inborn genetic diseases	Uncertain significance (May 31, 2019)
X-123184561-A-C			Uncertain significance (Aug 10, 2023)
X-123184570-T-C			Uncertain significance (Jan 04, 2024)
X-123184573-G-A		Inborn genetic diseases	Uncertain significance (Feb 14, 2024)
X-123184575-G-A		Inborn genetic diseases	Uncertain significance (Feb 13, 2023)
X-123184577-G-A			Likely benign (Apr 24, 2023)
X-123184578-G-A			Conflicting classifications of pathogenicity (Jun 29, 2023)
X-123184590-G-A			Uncertain significance (Jun 13, 2022)
X-123184592-C-A		GRIA3-related disorder	Likely benign (Mar 23, 2023)
X-123184599-C-A			Uncertain significance (Oct 24, 2023)
X-123184599-C-T			Likely benign (Apr 18, 2023)
X-123184601-T-G			Likely benign (Jun 18, 2023)
X-123184603-T-G			Uncertain significance (Nov 19, 2022)
X-123184604-G-A		Syndromic X-linked intellectual disability 94	Conflicting classifications of pathogenicity (Jul 19, 2022)
X-123184604-G-C		Inborn genetic diseases	Conflicting classifications of pathogenicity (Jan 17, 2024)
X-123184608-C-T			Uncertain significance (Sep 10, 2023)
X-123184611-T-A			Uncertain significance (Jun 18, 2023)
X-123184622-A-T			Benign (Dec 18, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GRIA3	protein_coding	protein_coding	ENST00000264357	15	306761

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.000241	125704	2	3	125709	0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.23	130	354	0.368	0.0000270	5888
Missense in Polyphen		40	161.29	0.248		2707
Synonymous	0.302	131	135	0.967	0.0000112	1698
Loss of Function	4.97	2	32.6	0.0613	0.00000259	531

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000760	0.0000615
Ashkenazi Jewish	0.000134	0.0000992
East Asian	0.0000723	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000245	0.0000176
Middle Eastern	0.0000723	0.0000544
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L- glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate. {ECO:0000269|PubMed:21172611}.
• Disease: DISEASE: Mental retardation, X-linked 94 (MRX94) [MIM:300699]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non- syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations. MRX94 patients have moderate mental retardation. Other variable features are macrocephaly, seizures, myoclonic jerks, autistic behavior, asthenic body habitus, distal muscle weakness and hyporeflexia. {ECO:0000269|PubMed:17989220}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Retrograde endocannabinoid signaling - Homo sapiens (human);Dopaminergic synapse - Homo sapiens (human);Glutamatergic synapse - Homo sapiens (human);Long-term depression - Homo sapiens (human);Nicotine addiction - Homo sapiens (human);Circadian entrainment - Homo sapiens (human);cAMP signaling pathway - Homo sapiens (human);Amphetamine addiction - Homo sapiens (human);Transcriptional misregulation in cancer - Homo sapiens (human);Neuroactive ligand-receptor interaction - Homo sapiens (human);Brain-Derived Neurotrophic Factor (BDNF) signaling pathway;Common Pathways Underlying Drug Addiction;Activation of AMPA receptors;Neuronal System;Synaptic adhesion-like molecules;Trafficking of GluR2-containing AMPA receptors;Trafficking of AMPA receptors;Glutamate binding, activation of AMPA receptors and synaptic plasticity;Neurotransmitter receptors and postsynaptic signal transmission;Transmission across Chemical Synapses;Unblocking of NMDA receptor, glutamate binding and activation;Activation of NMDA receptor and postsynaptic events;Protein-protein interactions at synapses (Consensus)

Recessive Scores

• pRec: 0.176

Intolerance Scores

• loftool: 0.107
• rvis_EVS: -0.12
• rvis_percentile_EVS: 45.13

Haploinsufficiency Scores

• pHI: 0.405
• hipred: Y
• hipred_score: 0.768
• ghis: 0.568

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.652

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Gria3
• Phenotype: integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); 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); 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); reproductive system phenotype

Zebrafish Information Network

• Gene name: gria3a
• Affected structure: whole organism
• Phenotype tag: abnormal
• Phenotype quality: dead

Gene ontology

• Biological process: glutamate receptor signaling pathway;ion transmembrane transport;ionotropic glutamate receptor signaling pathway;regulation of postsynaptic membrane potential
• Cellular component: plasma membrane;cell junction;endocytic vesicle membrane;AMPA glutamate receptor complex;postsynaptic membrane;parallel fiber to Purkinje cell synapse
• Molecular function: amyloid-beta binding;AMPA glutamate receptor activity;transmitter-gated ion channel activity involved in regulation of postsynaptic membrane potential