IGF1R

Chr 15ADAR

insulin like growth factor 1 receptor

Also known as: CD221, IGFIR, IGFR, JTK13

NCBI Gene: 3480 ENSG00000140443 UniProt: P08069 OMIM: 147370

The IGF1R protein is a receptor tyrosine kinase that binds insulin-like growth factor 1 and mediates critical cell growth and survival signaling pathways including PI3K-AKT and Ras-MAPK. Mutations cause insulin-like growth factor 1 resistance, which can be inherited in either autosomal dominant or autosomal recessive patterns. The gene is highly constrained against loss-of-function variants (pLI 0.97), indicating that complete loss of function is typically not tolerated.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This receptor binds insulin-like growth factor with a high affinity. It has tyrosine kinase activity. The insulin-like growth factor I receptor plays a critical role in transformation events. Cleavage of the precursor generates alpha and beta subunits. It is highly overexpressed in most malignant tissues where it functions as an anti-apoptotic agent by enhancing cell survival. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Insulin-like growth factor I, resistance toMIM #270450

ADAR

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Insulin-like growth factor I, resistance to; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

508

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.31

LOEUF· LoF intol.

LOF*

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.31LOEUF

pLI 0.968

Z-score 5.99

OE 0.19 (0.12–0.31)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.73Z-score

OE missense 0.73 (0.69–0.78)

609 obs / 830.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.19 (0.12–0.31)

0≤0.351.4

Missense OE?0.73 (0.69–0.78)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 12 / 63.6Missense obs/exp: 609 / 830.3Syn Z: -2.08

Background carrier burden — how many people carry a rare variant somewhere in IGF1R?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 46

1,447 rare PASS variants

Rare truncating (LoF)

1 in 3,200

107 rare PASS variants

Rare synonymous (reference)

1 in 42

838 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for IGF1R. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 60	1 in 2,600
South Asian	~43k	1 in 46	1 in 7,200
Remaining (unassigned)	~30k	1 in 35	1 in 3,000
European (Finnish)	~27k	1 in 110	1 in 2,900
Admixed American	~22k	1 in 45	1 in 2,000
African / African American	~21k	1 in 40	1 in 3,300
East Asian	~20k	1 in 57	1 in 3,300
Ashkenazi Jewish	~13k	1 in 130	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 37	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 18 of 21 coding exons well covered in gnomAD exomes; exons 14, 15, 17 marginal. Genomes: all 21.? see exons ↓