IGF1R

insulin like growth factor 1 receptor, the group of Fibronectin type III domain containing|MicroRNA protein coding host genes|CD molecules|Receptor tyrosine kinases

Basic information

Region (hg38): 15:98648539-98964530

Links

ENSG00000140443 ∙ NCBI:3480 ∙ OMIM:147370 ∙ HGNC:5465 ∙ Uniprot:P08069 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• growth delay due to insulin-like growth factor I resistance (Definitive), mode of inheritance: AR
• growth delay due to insulin-like growth factor I resistance (Definitive), mode of inheritance: AD
• growth delay due to insulin-like growth factor I resistance (Supportive), mode of inheritance: AD
• growth delay due to insulin-like growth factor I resistance (Strong), mode of inheritance: AR
• growth delay due to insulin-like growth factor I resistance (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Insulin-like growth factor I, resistance to	AD/AR	Endocrine	Individuals may manifest with severe growth deficiency, and growth hormone therapy (starting at a relatively early age) can be beneficial	Endocrine	14657428; 22998174; 22130793; 23045302
Bi-allelic variants have been described as resulting in a more severe phenotype

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the IGF1R gene.

• not provided (13 variants)
• Growth delay due to insulin-like growth factor I resistance (4 variants)
• Inborn genetic diseases (4 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the IGF1R gene is commonly pathogenic or not.

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.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous	1		7	161	23	192
missense	1	10	274	11	1	297
nonsense	5	5	1			11
start loss		1				1
frameshift	10	5	3			18
inframe indel		2	3			5
splice donor/acceptor (+/-2bp)	3	3	1			7
splice region			18	13		31
non coding			238	94	56	388
Total	20	26	527	266	80

Highest pathogenic variant AF is 0.00000657

Variants in IGF1R

This is a list of pathogenic ClinVar variants found in the IGF1R region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
15-98649525-CTTTTTTTTT-C		Growth delay due to insulin-like growth factor I resistance	Benign/Likely benign (Nov 16, 2021)
15-98649531-T-C		Growth delay due to insulin-like growth factor I resistance	Benign (Jan 13, 2018)
15-98649539-T-C		Growth delay due to insulin-like growth factor I resistance	Uncertain significance (Jan 13, 2018)
15-98649578-A-G		not specified • IGF1R-related disorder	Uncertain significance (Mar 28, 2024)
15-98649583-T-A		Growth delay due to insulin-like growth factor I resistance	Likely pathogenic (Jun 09, 2023)
15-98649596-C-T			Benign (Jan 30, 2024)
15-98649597-G-A			Likely benign (Jun 01, 2024)
15-98649609-C-T			Uncertain significance (Aug 04, 2023)
15-98649616-C-G		Inborn genetic diseases	Uncertain significance (Jun 16, 2023)
15-98649621-TG-T			Pathogenic (Jun 27, 2023)
15-98649624-G-A		Growth delay due to insulin-like growth factor I resistance	Uncertain significance (Oct 15, 2019)
15-98649629-C-A			Likely benign (Aug 25, 2023)
15-98649636-C-T			Uncertain significance (Sep 01, 2023)
15-98649640-C-T		Inborn genetic diseases	Uncertain significance (Jun 07, 2023)
15-98649641-C-T			Likely benign (Jun 07, 2023)
15-98649652-C-G		Inborn genetic diseases	Uncertain significance (Oct 26, 2022)
15-98649652-C-T		Growth delay due to insulin-like growth factor I resistance	Uncertain significance (Jan 05, 2023)
15-98649656-C-T			Likely benign (Oct 01, 2022)
15-98649658-G-A		Neurodevelopmental disorder	Likely pathogenic (Aug 06, 2020)
15-98649661-C-T			Uncertain significance (Aug 29, 2022)
15-98649665-G-A		Growth delay due to insulin-like growth factor I resistance • IGF1R-related disorder	Conflicting classifications of pathogenicity (Mar 03, 2023)
15-98649674-AAGTG-A			Uncertain significance (Nov 15, 2023)
15-98649682-A-G		IGF1R-related disorder	Likely benign (Jul 31, 2018)
15-98649682-ATG-A			Likely benign (Feb 19, 2023)
15-98649689-C-T		Growth delay due to insulin-like growth factor I resistance	Benign (Jan 30, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
IGF1R	protein_coding	protein_coding	ENST00000268035	21	315560

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.968	0.0320	125715	0	33	125748	0.000131

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.73	609	830	0.734	0.0000570	9025
Missense in Polyphen		130	332.69	0.39075		3823
Synonymous	-2.08	399	350	1.14	0.0000272	2638
Loss of Function	5.99	12	63.6	0.189	0.00000343	738

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000397	0.000395
Ashkenazi Jewish	0.00	0.00
East Asian	0.000164	0.000163
Finnish	0.000185	0.000185
European (Non-Finnish)	0.000124	0.000105
Middle Eastern	0.000164	0.000163
South Asian	0.000165	0.000163
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and insulin (INS) with a lower affinity. The activated IGF1R is involved in cell growth and survival control. IGF1R is crucial for tumor transformation and survival of malignant cell. Ligand binding activates the receptor kinase, leading to receptor autophosphorylation, and tyrosines phosphorylation of multiple substrates, that function as signaling adapter proteins including, the insulin-receptor substrates (IRS1/2), Shc and 14-3-3 proteins. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway and the Ras-MAPK pathway. The result of activating the MAPK pathway is increased cellular proliferation, whereas activating the PI3K pathway inhibits apoptosis and stimulates protein synthesis. Phosphorylated IRS1 can activate the 85 kDa regulatory subunit of PI3K (PIK3R1), leading to activation of several downstream substrates, including protein AKT/PKB. AKT phosphorylation, in turn, enhances protein synthesis through mTOR activation and triggers the antiapoptotic effects of IGFIR through phosphorylation and inactivation of BAD. In parallel to PI3K- driven signaling, recruitment of Grb2/SOS by phosphorylated IRS1 or Shc leads to recruitment of Ras and activation of the ras-MAPK pathway. In addition to these two main signaling pathways IGF1R signals also through the Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT). Phosphorylation of JAK proteins can lead to phosphorylation/activation of signal transducers and activators of transcription (STAT) proteins. In particular activation of STAT3, may be essential for the transforming activity of IGF1R. The JAK/STAT pathway activates gene transcription and may be responsible for the transforming activity. JNK kinases can also be activated by the IGF1R. IGF1 exerts inhibiting activities on JNK activation via phosphorylation and inhibition of MAP3K5/ASK1, which is able to directly associate with the IGF1R.
• Disease: DISEASE: Insulin-like growth factor 1 resistance (IGF1RES) [MIM:270450]: A disorder characterized by intrauterine growth retardation, poor postnatal growth and increased plasma IGF1 levels. {ECO:0000269|PubMed:14657428, ECO:0000269|PubMed:15928254, ECO:0000269|PubMed:25040157}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: PI3K-Akt signaling pathway - Homo sapiens (human);Focal adhesion - Homo sapiens (human);mTOR signaling pathway - Homo sapiens (human);Adherens junction - Homo sapiens (human);Melanoma - Homo sapiens (human);Oocyte meiosis - Homo sapiens (human);HIF-1 signaling pathway - Homo sapiens (human);Endocytosis - Homo sapiens (human);Longevity regulating pathway - multiple species - Homo sapiens (human);Long-term depression - Homo sapiens (human);Breast cancer - Homo sapiens (human);Autophagy - animal - Homo sapiens (human);FoxO signaling pathway - Homo sapiens (human);AMPK signaling pathway - Homo sapiens (human);Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human);Hepatocellular carcinoma - Homo sapiens (human);Glioma - Homo sapiens (human);Prostate cancer - Homo sapiens (human);Longevity regulating pathway - Homo sapiens (human);Rap1 signaling pathway - Homo sapiens (human);Ras signaling pathway - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Proteoglycans in cancer - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Transcriptional misregulation in cancer - Homo sapiens (human);Ovarian steroidogenesis - Homo sapiens (human);Progesterone-mediated oocyte maturation - Homo sapiens (human);EGF-Core;IGF-Core;MicroRNAs in cardiomyocyte hypertrophy;Human Thyroid Stimulating Hormone (TSH) signaling pathway;Signaling Pathways in Glioblastoma;Apoptosis;JAK-STAT;Focal Adhesion;Apoptotic Signaling Pathway;Factors and pathways affecting insulin-like growth factor (IGF1)-Akt signaling;Focal Adhesion-PI3K-Akt-mTOR-signaling pathway;PI3K-Akt Signaling Pathway;Ebola Virus Pathway on Host;Somatroph axis (GH) and its relationship to dietary restriction and aging;Ebola Virus Pathway on Host;Ras Signaling;Endochondral Ossification;Insulin Signaling;Senescence and Autophagy in Cancer;Signal Transduction;regulation of bad phosphorylation;multiple antiapoptotic pathways from igf-1r signaling lead to bad phosphorylation;skeletal muscle hypertrophy is regulated via akt-mtor pathway;igf-1 signaling pathway;IGF signaling;IL-7 signaling;SHP2 signaling;the igf-1 receptor and longevity;JAK STAT pathway and regulation;Posttranslational regulation of adherens junction stability and dissassembly;EPO signaling;Leptin;SHC-related events triggered by IGF1R;TSH;IRS-related events triggered by IGF1R;IGF1R signaling cascade;Signaling by Receptor Tyrosine Kinases;VEGF;Stabilization and expansion of the E-cadherin adherens junction;IGF1 pathway;Plasma membrane estrogen receptor signaling;Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R);Integrins in angiogenesis (Consensus)

Recessive Scores

• pRec: 0.862

Intolerance Scores

• loftool: 0.107
• rvis_EVS: -1.72
• rvis_percentile_EVS: 2.49

Haploinsufficiency Scores

• pHI: 0.995
• hipred: Y
• hipred_score: 0.706
• ghis: 0.543

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.998

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Igf1r
• Phenotype: reproductive system phenotype; 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); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; neoplasm; embryo phenotype; respiratory system phenotype; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); immune system phenotype; skeleton phenotype; hearing/vestibular/ear 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); limbs/digits/tail phenotype; craniofacial 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); growth/size/body region phenotype; endocrine/exocrine gland phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); cellular phenotype; homeostasis/metabolism phenotype; muscle phenotype

Zebrafish Information Network

• Gene name: igf1rb
• Affected structure: retinal ganglion cell
• Phenotype tag: abnormal
• Phenotype quality: absent

Gene ontology

• Biological process: immune response;signal transduction;transmembrane receptor protein tyrosine kinase signaling pathway;positive regulation of cell population proliferation;insulin receptor signaling pathway;phosphatidylinositol 3-kinase signaling;positive regulation of phosphatidylinositol 3-kinase signaling;positive regulation of cell migration;peptidyl-tyrosine autophosphorylation;glucose homeostasis;negative regulation of apoptotic process;positive regulation of protein complex disassembly;positive regulation of MAPK cascade;regulation of JNK cascade;protein autophosphorylation;insulin-like growth factor receptor signaling pathway;phosphatidylinositol-mediated signaling;anatomical structure development;protein tetramerization;inactivation of MAPKK activity;positive regulation of protein kinase B signaling;cellular response to glucose stimulus;dendritic spine maintenance;amyloid-beta clearance;positive regulation of cold-induced thermogenesis;cellular response to amyloid-beta
• Cellular component: plasma membrane;integral component of plasma membrane;insulin receptor complex;membrane;axon;alphav-beta3 integrin-IGF-1-IGF1R complex;intracellular membrane-bounded organelle;receptor complex
• Molecular function: protein tyrosine kinase activity;transmembrane receptor protein tyrosine kinase activity;insulin-activated receptor activity;insulin-like growth factor-activated receptor activity;insulin receptor binding;protein binding;insulin-like growth factor binding;ATP binding;insulin-like growth factor I binding;identical protein binding;phosphatidylinositol 3-kinase binding;insulin binding;insulin receptor substrate binding