ASIP

protein-coding

agouti signaling protein

Gene summary

In mice, the agouti gene encodes a paracrine signaling molecule that causes hair follicle melanocytes to synthesize pheomelanin, a yellow pigment, instead of the black or brown pigment, eumelanin. Pleiotropic effects of constitutive expression of the mouse gene include adult-onset obesity, increased tumor susceptibility, and premature infertility. This gene is highly similar to the mouse gene and encodes a secreted protein that may (1) affect the quality of hair pigmentation, (2) act as a pharmacological antagonist of alpha-melanocyte-stimulating hormone, (3) play a role in neuroendocrine aspects of melanocortin action, and (4) have a functional role in regulating lipid metabolism in adipocytes. [provided by RefSeq, Jul 2008]

Previous symbols:

AGTIL

MANE transcript

NM_001672.3

Inheritance

ClinVar variants

U:34B:18

Top phenotype

Obesity and hypopigmentation; Skin/hair/eye pigmentation 9

gnomAD constraint

pLI —, LoF o/e 0.65

Max pathogenic AF

—

Genomic locus

chr20:34,194,569-34,269,344

External References & Databases

Ensembl (ENSG00000101440)

Transcript & Mutation Effects

hg38 • Region Span ~74.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

Clinical Genomic Database (CGD)

Obesity and hypopigmentation; Skin/hair/eye pigmentation 9AD

Manifestation: Dermatologic; 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

Refs: 11833005; 18488028; 36536132

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ASIP variants in ClinVar

3 Conditions Cataloged

ASIP-related conditionTotal: 51

not specifiedTotal: 20

not providedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001672.3. 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			1 clinvar	15 clinvar	1 clinvar	17
missense			31 clinvar	2 clinvar		33
nonsense			1 clinvar			1
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)						0
Total	0	0	34	17	1	52

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 11 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001672.3	RefSeq	NP_001663.2	3	MANE Select
ENST00000374954.4	Ensembl	ENSP00000364092.3	3	MANE Select
NM_001385218.1	RefSeq	NP_001372147.1	3	Standard
ENST00000568305.5	Ensembl	ENSP00000454804.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
asip2b	Danio rerio	Structure: melanocyte Quality: dispersed abnormal

Gene / Model

Organism

Observed Phenotype

asip2b

Danio rerio

Structure: melanocyte

Quality: dispersed

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Melanogenesis - Homo sapiens (human)
Adipogenesis
Insulin-mediated glucose transport

Biological Process

generation of precursor metabolites and energy
signal transduction
cell-cell signaling
adult feeding behavior
hormone-mediated signaling pathway

Molecular Function

signaling receptor binding
type 3 melanocortin receptor binding
type 4 melanocortin receptor binding

Cellular Component

extracellular space
cell

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000568305
Coding exons: 3
Length: 74776
Individuals with no LoFs: 125736
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 125747
p: 0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.119	77	80.0	0.962	0.00000481	844
Missense (PolyPhen)		37	39.827	0.92902		424
Synonymous	0.734	27	32.3	0.836	0.00000185	270
Loss of Function	0.708	3	4.65	0.646	2.81e-7	53

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000059	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000050	0.000046	rare
European (Non-Finnish)	0.000057	0.000053	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the regulation of melanogenesis. The binding of ASP to MC1R precludes alpha-MSH initiated signaling and thus blocks production of cAMP, leading to a down-regulation of eumelanogenesis (brown/black pigment) and thus increasing synthesis of pheomelanin (yellow/red pigment). In higher primates, agouti may affect the quality of hair pigmentation rather than its pattern of deposition. Could well play a role in neuroendocrine aspects of melanocortin action. May have some functional role in regulating the lipid metabolism with adipocytes.;

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.141

Gene Damage Prediction

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