DLG4

discs large MAGUK scaffold protein 4, the group of PDZ domain containing|Membrane associated guanylate kinases

Basic information

Region (hg38): 17:7187187-7219836

Links

ENSG00000132535 ∙ NCBI:1742 ∙ OMIM:602887 ∙ HGNC:2903 ∙ Uniprot:P78352 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• intellectual developmental disorder 62 (Strong), mode of inheritance: AD
• intellectual developmental disorder 62 (Strong), mode of inheritance: AD
• intellectual developmental disorder 62 (Strong), mode of inheritance: AD
• complex neurodevelopmental disorder (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Intellectual developmental disorder, autosomal dominant 62	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; Musculoskeletal; Neurologic	20952458; 27479843; 29460436

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the DLG4 gene.

• Intellectual_developmental_disorder_62 (112 variants)
• not_provided (111 variants)
• Inborn_genetic_diseases (35 variants)
• DLG4-related_disorder (18 variants)
• not_specified (10 variants)
• Intellectual_disability (4 variants)
• Marfanoid_habitus_and_intellectual_disability (3 variants)
• Neurodevelopmental_delay (2 variants)
• Cerebral_visual_impairment_and_intellectual_disability (1 variants)
• Intellectual_disability-epilepsy-extrapyramidal_syndrome (1 variants)
• ACADVL-related_disorder (1 variants)
• Intellectual_disability,_autosomal_dominant_24 (1 variants)
• Neurodevelopmental_abnormality (1 variants)
• DLG4-related_synaptopathy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the DLG4 gene is commonly pathogenic or not. These statistics are base on transcript: NM_001321075.3. 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	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous		3	1	18	2	24
missense	4	6	102	7		119
nonsense	21	5				26
start loss						0
frameshift	27	11	2			40
splice donor/acceptor (+/-2bp)	5	18	6			29
Total	57	43	111	25	2

Highest pathogenic variant AF is 7.8373836e-7

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
DLG4	protein_coding	protein_coding	ENST00000399510	22	29813

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.000460	124512	0	7	124519	0.0000281

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.93	174	477	0.365	0.0000306	4985
Missense in Polyphen		69	282.81	0.24398		2862
Synonymous	0.823	182	197	0.925	0.0000134	1503
Loss of Function	5.46	5	44.1	0.113	0.00000256	479

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000274	0.000259
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000290	0.0000266
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Interacts with the cytoplasmic tail of NMDA receptor subunits and shaker-type potassium channels. Required for synaptic plasticity associated with NMDA receptor signaling. Overexpression or depletion of DLG4 changes the ratio of excitatory to inhibitory synapses in hippocampal neurons. May reduce the amplitude of ASIC3 acid-evoked currents by retaining the channel intracellularly. May regulate the intracellular trafficking of ADR1B. Also regulates AMPA-type glutamate receptor (AMPAR) immobilization at postsynaptic density keeping the channels in an activated state in the presence of glutamate and preventing synaptic depression. {ECO:0000250|UniProtKB:Q62108}.
• Pathway: Glutamatergic synapse - Homo sapiens (human);Huntington,s disease - Homo sapiens (human);Hippo signaling pathway - Homo sapiens (human);Cocaine addiction - Homo sapiens (human);BDNF-TrkB Signaling;NO-cGMP-PKG mediated Neuroprotection;Developmental Biology;Signal Transduction;nitric oxide signaling pathway;Activation of Ca-permeable Kainate Receptor;Ionotropic activity of kainate receptors;Activation of kainate receptors upon glutamate binding;NrCAM interactions;Neuronal System;Synaptic adhesion-like molecules;ErbB4 signaling events;RHO GTPases activate CIT;RHO GTPase Effectors;Signaling by Rho GTPases;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;Neurexins and neuroligins;Trafficking of AMPA receptors;L1CAM interactions;Glutamate binding, activation of AMPA receptors and synaptic plasticity;Neurotransmitter receptors and postsynaptic signal transmission;Transmission across Chemical Synapses;Axon guidance;Ras activation upon Ca2+ influx through NMDA receptor;CREB phosphorylation through the activation of Ras;Unblocking of NMDA receptor, glutamate binding and activation;CREB phosphorylation through the activation of CaMKII;Post NMDA receptor activation events;Activation of NMDA receptor and postsynaptic events;Protein-protein interactions at synapses;LGI-ADAM interactions (Consensus)

Recessive Scores

• pRec: 0.611

Intolerance Scores

• loftool: 0.424
• rvis_EVS: -0.67
• rvis_percentile_EVS: 15.76

Haploinsufficiency Scores

• pHI: 0.983
• hipred: Y
• hipred_score: 0.613
• ghis: 0.691

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.710

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Dlg4
• 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); 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); 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); homeostasis/metabolism phenotype; endocrine/exocrine gland phenotype

Gene ontology

• Biological process: MAPK cascade;negative regulation of receptor internalization;signal transduction;positive regulation of cytosolic calcium ion concentration;chemical synaptic transmission;nervous system development;learning;synaptic vesicle maturation;protein localization to synapse;cellular response to potassium ion;receptor clustering;establishment of protein localization;regulation of long-term neuronal synaptic plasticity;positive regulation of synaptic transmission;dendritic spine morphogenesis;positive regulation of protein tyrosine kinase activity;protein-containing complex assembly;AMPA glutamate receptor clustering;receptor localization to synapse;cell-cell adhesion;postsynaptic neurotransmitter receptor diffusion trapping;positive regulation of neuron projection arborization;regulation of NMDA receptor activity;positive regulation of excitatory postsynaptic potential
• Cellular component: cytoplasm;endoplasmic reticulum;cytosol;plasma membrane;synaptic vesicle;voltage-gated potassium channel complex;ionotropic glutamate receptor complex;postsynaptic density;cell junction;endocytic vesicle membrane;cortical cytoskeleton;extrinsic component of cytoplasmic side of plasma membrane;neuromuscular junction;AMPA glutamate receptor complex;dendrite cytoplasm;neuron projection;dendritic spine;juxtaparanode region of axon;neuron projection terminus;neuron spine;synapse;postsynaptic membrane;excitatory synapse;postsynaptic density membrane
• Molecular function: Ras guanyl-nucleotide exchange factor activity;protein binding;protein C-terminus binding;kinase binding;protein phosphatase binding;PDZ domain binding;beta-1 adrenergic receptor binding;D1 dopamine receptor binding;P2Y1 nucleotide receptor binding;acetylcholine receptor binding;ionotropic glutamate receptor binding;protein-containing complex binding;neuroligin family protein binding;scaffold protein binding