GeneBe

IGF1

protein-coding

insulin like growth factor 1, the group of Neuropeptides

Gene summary

The protein encoded by this gene is similar to insulin in function and structure and is a member of a family of proteins involved in mediating growth and development. The encoded protein is processed from a precursor, bound by a specific receptor, and secreted. Defects in this gene are a cause of insulin-like growth factor I deficiency. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar processing to generate mature protein. [provided by RefSeq, Sep 2015]

MANE transcript

NM_000618.5

Inheritance

SD, AR, AD

ClinVar variants

P:11U:34B:22

Top phenotype

Insulin-like growth factor I deficiency

gnomAD constraint

pLI —, LoF o/e 0.26

Max pathogenic AF

—

Genomic locus

chr12:102,395,874-102,481,744

External References & Databases

Ensembl (ENSG00000017427)NCBI Gene (3479)OMIM (147440)HGNC:5464GenCCUniProt (P05019)AlphaFoldClinVar (IGF1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~85.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

growth delay due to insulin-like growth factor type 1 deficiencySTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0012110

Submitter: PanelApp Australia

growth delay due to insulin-like growth factor type 1 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012110

Submitter: G2P

growth delay due to insulin-like growth factor type 1 deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012110

Submitter: Orphanet

growth delay due to insulin-like growth factor type 1 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012110

Submitter: Labcorp Genetics (formerly Invitae)

growth delay due to insulin-like growth factor type 1 deficiencyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012110

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Insulin-like growth factor I deficiencyAR

Manifestation: Audiologic/Otolaryngologic; Endocrine; Neurologic

Intervention: Audiologic/Otolaryngologic; Endocrine

Rationale: Recombinant human IGF1 treatment has been reported to improve linear growth and insulin sensitivity; Interventions related to hearing impairment may also be beneficial

Refs: 8857020; 10323388; 10770174; 14684690; 20668042; 21237682; 22832530Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IGF1 variants in ClinVar

8 Conditions Cataloged
not providedTotal: 57
Growth delay due to insulin-like growth factor type 1 deficiencyTotal: 15
not specifiedTotal: 13
Inborn genetic diseasesTotal: 9
IGF1-related disorderTotal: 4
Monogenic short statueTotal: 3
MicrocephalyTotal: 1
Intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000618.5. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
20
clinvar
 21
missense
1
clinvar
31
clinvar
2
clinvar
 34
nonsense
1
clinvar
1
clinvar
 2
start loss
0
frameshift
3
clinvar
2
clinvar
2
clinvar
 7
splice donor/acceptor (+/-2bp)
3
clinvar
 3
Total473422067

Highest pathogenic variant AF is 0.0000013696529

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 33 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000618.5RefSeqNP_000609.14MANE Select
ENST00000337514.11EnsemblENSP00000337612.74MANE Select
NM_001111283.3RefSeqNP_001104753.15Standard
NM_001111284.2RefSeqNP_001104754.14Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
igf1Danio rerio

Structure: whole organism

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • PI3K-Akt signaling pathway - Homo sapiens (human)
  • Inflammatory mediator regulation of TRP channels - Homo sapiens (human)
  • Focal adhesion - Homo sapiens (human)
  • mTOR signaling pathway - Homo sapiens (human)
  • Melanoma - Homo sapiens (human)

Biological Process

  • activation of MAPK activity
  • skeletal system development
  • cell activation
  • platelet degranulation
  • signal transduction

Molecular Function

  • insulin receptor binding
  • insulin-like growth factor receptor binding
  • integrin binding
  • hormone activity
  • protein binding

Cellular Component

  • extracellular region
  • extracellular space
  • insulin-like growth factor binding protein complex
  • platelet alpha granule lumen
  • alphav-beta3 integrin-IGF-1-IGF1R complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000307046
Coding exons
4
Length
84779
Individuals with no LoFs
124431
Homozygous LoFs
0
Heterozygous LoFs
6
Defined
124437
p
0.0000241
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.54681140.5950.000006651272
Missense (PolyPhen)1748.2930.35202481
Synonymous-0.5815146.01.110.00000298373
Loss of Function1.9327.810.2563.31e-7105

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000650.000065rare
Latino/Admixed American0.0000610.000058rare
Ashkenazi Jewish00.0absent
East Asian0.0000580.000056rare
Finnish0.0000460.000046rare
European (Non-Finnish)0.00000910.0000089rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: The insulin-like growth factors, isolated from plasma, are structurally and functionally related to insulin but have a much higher growth-promoting activity. May be a physiological regulator of [1-14C]-2-deoxy-D-glucose (2DG) transport and glycogen synthesis in osteoblasts. Stimulates glucose transport in bone-derived osteoblastic (PyMS) cells and is effective at much lower concentrations than insulin, not only regarding glycogen and DNA synthesis but also with regard to enhancing glucose uptake. May play a role in synapse maturation (PubMed:21076856, PubMed:24132240). Ca(2+)-dependent exocytosis of IGF1 is required for sensory perception of smell in the olfactory bulb (By similarity). Acts as a ligand for IGF1R. Binds to the alpha subunit of IGF1R, leading to the activation of the intrinsic tyrosine kinase activity which autophosphorylates tyrosine residues in the beta subunit thus initiatiating a cascade of down- stream signaling events leading to activation of the PI3K-AKT/PKB and the Ras-MAPK pathways. Binds to integrins ITGAV:ITGB3 and ITGA6:ITGB4. Its binding to integrins and subsequent ternary complex formation with integrins and IGFR1 are essential for IGF1 signaling. Induces the phosphorylation and activation of IGFR1, MAPK3/ERK1, MAPK1/ERK2 and AKT1 (PubMed:19578119, PubMed:22351760, PubMed:23696648, PubMed:23243309). {ECO:0000250|UniProtKB:P05017, ECO:0000269|PubMed:19578119, ECO:0000269|PubMed:21076856, ECO:0000269|PubMed:22351760, ECO:0000269|PubMed:23243309, ECO:0000269|PubMed:23696648, ECO:0000269|PubMed:24132240}.;
Disease
DISEASE: Insulin-like growth factor I deficiency (IGF1 deficiency) [MIM:608747]: Autosomal recessive disorder characterized by growth retardation, sensorineural deafness and mental retardation. {ECO:0000269|PubMed:8857020}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.994

Intolerance Scores

LoFtool
0.128
RVIS EVS
0.24
RVIS percentile EVS
68.98

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
K
Indispensability pred.
E
Indispensability score
0.852

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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