GRM4

protein-coding

glutamate metabotropic receptor 4, the group of Glutamate metabotropic receptors

Gene summary

L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. The metabotropic glutamate receptors are a family of G protein-coupled receptors, that have been divided into 3 groups on the basis of sequence homology, putative signal transduction mechanisms, and pharmacologic properties. Group I includes GRM1 and GRM5 and these receptors have been shown to activate phospholipase C. Group II includes GRM2 and GRM3 while Group III includes GRM4, GRM6, GRM7 and GRM8. Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2012]

MANE transcript

NM_000841.4

Inheritance

—

ClinVar variants

U:129B:10

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.14

Max pathogenic AF

—

Genomic locus

chr6:34,018,643-34,155,622

External References & Databases

Ensembl (ENSG00000124493)

Transcript & Mutation Effects

hg38 • Region Span ~137.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GRM4 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 123

not providedTotal: 15

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000841.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	2 clinvar	7 clinvar	11
missense			125 clinvar		1 clinvar	126
nonsense						0
start loss			1 clinvar			1
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)						0
Total	0	0	129	2	8	139

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000841.4	RefSeq	NP_000832.1	10	MANE Select
ENST00000538487.7	Ensembl	ENSP00000440556.1	10	MANE Select
NM_001256809.3	RefSeq	NP_001243738.1	9	Standard
NM_001256811.3	RefSeq	NP_001243740.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glutamatergic synapse - Homo sapiens (human)
Phospholipase D signaling pathway - Homo sapiens (human)
Neuroactive ligand-receptor interaction - Homo sapiens (human)
Taste transduction - Homo sapiens (human)
GPCRs, Class C Metabotropic glutamate, pheromone

Biological Process

activation of MAPK activity
G protein-coupled receptor signaling pathway
adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway
G protein-coupled glutamate receptor signaling pathway
chemical synaptic transmission

Molecular Function

G protein-coupled receptor activity
glutamate receptor activity

Cellular Component

plasma membrane
integral component of plasma membrane
cytoplasmic vesicle
presynaptic membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000538487
Coding exons: 10
Length: 133772
Individuals with no LoFs: 125720
Homozygous LoFs: 0
Heterozygous LoFs: 26
Defined: 125746
p: 0.000103

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.68	447	638	0.701	0.0000443	5933
Missense (PolyPhen)		179	296.3	0.60412		2805
Synonymous	1.03	251	273	0.921	0.0000204	1892
Loss of Function	4.86	5	36.9	0.136	0.00000194	380

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000063	0.000062	rare
South Asian	0.00052	0.00052	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling inhibits adenylate cyclase activity. {ECO:0000269|PubMed:7617140, ECO:0000269|PubMed:8738157, ECO:0000269|PubMed:9473604}.;

Recessive Scores

pRec: 0.198

Intolerance Scores

LoFtool: 0.0353
RVIS EVS: -2.48
RVIS percentile EVS: 0.96

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.453

Gene Damage Prediction

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