MC4R

protein-coding

melanocortin 4 receptor, the group of Melanocortin receptors

Gene summary

The protein encoded by this gene is a membrane-bound receptor and member of the melanocortin receptor family. The encoded protein interacts with adrenocorticotropic and MSH hormones and is mediated by G proteins. This is an intronless gene. Defects in this gene are a cause of autosomal dominant obesity. [provided by RefSeq, Jan 2010]

MANE transcript

NM_005912.3

Inheritance

AD, SD

ClinVar variants

P:98U:201B:56

Top phenotype

Obesity, autosomal dominant

gnomAD constraint

pLI —, LoF o/e 0.79

Max pathogenic AF

—

Genomic locus

chr18:60,371,062-60,372,775

External References & Databases

Ensembl (ENSG00000166603)

Transcript & Mutation Effects

hg38 • Region Span ~1.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

inherited obesitySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0019182

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

obesity due to melanocortin 4 receptor deficiencySTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0019115

Submitter: PanelApp Australia

obesity due to melanocortin 4 receptor deficiencySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019115

Submitter: Orphanet

Clinical Genomic Database (CGD)

Obesity, autosomal dominantAD

Manifestation: Endocrine

Intervention: General

Rationale: 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

Comments: Biallelic variants have been described

Refs: 9771698; 9771699; 10199800; 10577903; 11487744; 12646665; 12499395; 12646666; 14764818; 16507637; 16492696; 20957447; 20966905; 21047921; 21921657; 22463805

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MC4R variants in ClinVar

16 Conditions Cataloged

MC4R-related disorderTotal: 248

not providedTotal: 108

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20Total: 72

Early onset severe obesityTotal: 51

ObesityTotal: 48

not specifiedTotal: 29

Obesity due to melanocortin 4 receptor deficiencyTotal: 17

Monogenic diabetesTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005912.3. 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			5 clinvar	47 clinvar		52
missense	11 clinvar	46 clinvar	193 clinvar	8 clinvar	1 clinvar	259
nonsense	3 clinvar	10 clinvar	1 clinvar			14
start loss			1 clinvar			1
frameshift	7 clinvar	21 clinvar	1 clinvar			29
splice donor/acceptor (+/-2bp)						0
Total	21	77	201	55	1	355

Highest pathogenic variant AF is 0.00019204321

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005912.3	RefSeq	NP_005903.2	1	MANE Select
ENST00000299766.5	Ensembl	ENSP00000299766.3	1	MANE Select

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
mc4r	Danio rerio	Structure: whole organism Quality: increased length abnormal

Gene / Model

Organism

Observed Phenotype

mc4r

Danio rerio

Structure: whole organism

Quality: increased length

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Neuroactive ligand-receptor interaction - Homo sapiens (human)
Peptide GPCRs
GPCRs, Class A Rhodopsin-like
Signaling by GPCR
Signal Transduction

Biological Process

diet induced thermogenesis
energy reserve metabolic process
G protein-coupled receptor signaling pathway
adenylate cyclase-modulating G protein-coupled receptor signaling pathway
adenylate cyclase-activating G protein-coupled receptor signaling pathway

Molecular Function

melanocortin receptor activity
melanocyte-stimulating hormone receptor activity
protein binding
peptide hormone binding
ubiquitin protein ligase binding

Cellular Component

nucleus
plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000299766
Coding exons: 1
Length: 1438
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.01	218	180	1.21	0.00000960	2195
Missense (PolyPhen)		106	93.454	1.1343		1177
Synonymous	-0.852	78	69.0	1.13	0.00000384	664
Loss of Function	0.484	5	6.31	0.792	2.73e-7	97

Population LoF Frequency

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

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor specific to the heptapeptide core common to adrenocorticotropic hormone and alpha-, beta-, and gamma-MSH. Plays a central role in energy homeostasis and somatic growth. This receptor is mediated by G proteins that stimulate adenylate cyclase (cAMP). {ECO:0000269|PubMed:12646665, ECO:0000269|PubMed:25163632}.;

Recessive Scores

pRec: 0.561

Intolerance Scores

LoFtool: 0.771
RVIS EVS: -0.18
RVIS percentile EVS: 40.36

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.403

Gene Damage Prediction

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