GRIA4

glutamate ionotropic receptor AMPA type subunit 4, the group of Glutamate ionotropic receptor AMPA type subunits

Basic information

Region (hg38): 11:105609535-105982090

Previous symbols: [ "GLUR4" ]

Links

ENSG00000152578

∙ NCBI:2893 ∙ OMIM:138246 ∙ HGNC:4574 ∙ Uniprot:P48058 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

neurodevelopmental disorder with or without seizures and gait abnormalities (Limited), mode of inheritance: AD
neurodevelopmental disorder with or without seizures and gait abnormalities (Moderate), mode of inheritance: AD
neurodevelopmental disorder with or without seizures and gait abnormalities (Strong), mode of inheritance: AD
neurodevelopmental disorder with or without seizures and gait abnormalities (Moderate), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Neurodevelopmental disorder with or without seizures and gait abnormalities	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; Neurologic	29220673

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GRIA4 gene.

not_provided (101 variants)
Inborn_genetic_diseases (66 variants)
Neurodevelopmental_disorder_with_or_without_seizures_and_gait_abnormalities (46 variants)
GRIA4-related_disorder (18 variants)
Intellectual_disability (6 variants)
not_specified (5 variants)
See_cases (3 variants)
GRIA4-related_neurodevelopmental_disorder (2 variants)
Obesity (1 variants)
Autism_spectrum_disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GRIA4 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000000829.4. 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				15 clinvar	2 clinvar	17
missense	2 clinvar	7 clinvar	155 clinvar	9 clinvar		173
nonsense		2 clinvar	2 clinvar			4
start loss						0
frameshift			5 clinvar			5
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	2	9	165	24	2

Highest pathogenic variant AF is 0.0000329548

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GRIA4	protein_coding	protein_coding	ENST00000282499	16	372099

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0183	0.982	125728	0	20	125748	0.0000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.42	278	491	0.566	0.0000246	5907
Missense in Polyphen		75	213.31	0.35161		2612
Synonymous	-0.472	185	177	1.05	0.00000969	1731
Loss of Function	4.70	13	48.2	0.270	0.00000280	554

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000908	0.0000907
Ashkenazi Jewish	0.00	0.00
East Asian	0.000109	0.000109
Finnish	0.0000927	0.0000924
European (Non-Finnish)	0.000106	0.000105
Middle Eastern	0.000109	0.000109
South Asian	0.0000694	0.0000653
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: Neurodevelopmental disorder with or without seizures and gait abnormalities (NEDSGA) [MIM:617864]: An autosomal dominant neurodevelopmental disorder characterized by global developmental delay apparent from infancy or early childhood, mild to profound intellectual disability, hypertonia early in life, which progresses to spasticity and impaired gait later, and behavioral abnormalities. Some patients may develop seizures of variable severity early in life. {ECO:0000269|PubMed:29220673}. 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);Nicotine addiction - Homo sapiens (human);Circadian entrainment - Homo sapiens (human);cAMP signaling pathway - Homo sapiens (human);Amphetamine addiction - Homo sapiens (human);Neuroactive ligand-receptor interaction - Homo sapiens (human);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: 0.189

Intolerance Scores

loftool: 0.0934
rvis_EVS: -1.09
rvis_percentile_EVS: 7.05

Haploinsufficiency Scores

pHI: 0.250
hipred: Y
hipred_score: 0.750
ghis: 0.652

Essentials

essential_gene_CRISPR: N
essential_gene_CRISPR2: N
essential_gene_gene_trap: N
gene_indispensability_pred: E
gene_indispensability_score: 0.815

Gene Damage Prediction

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

Mouse Genome Informatics

Gene name: Gria4
Phenotype: homeostasis/metabolism phenotype; growth/size/body region 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); 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); vision/eye phenotype;

Gene ontology

Biological process: glutamate receptor signaling pathway;ion transmembrane transport;ionotropic glutamate receptor signaling pathway
Cellular component: plasma membrane;cell junction;endocytic vesicle membrane;AMPA glutamate receptor complex;neuronal cell body;dendritic spine;postsynaptic membrane;extracellular vesicle
Molecular function: amyloid-beta binding;ionotropic glutamate receptor activity;AMPA glutamate receptor activity