IHH
protein-codingIndian hedgehog signaling molecule, the group of Hedgehog signaling molecule family|MicroRNA protein coding host genes
Gene summary
This gene encodes a member of the hedgehog family of proteins. The encoded preproprotein is proteolytically processed to generate multiple protein products, including an N-terminal fragment that is involved in signaling. Hedgehog family proteins are essential secreted signaling molecules that regulate a variety of developmental processes including growth, patterning and morphogenesis. The protein encoded by this gene specifically plays a role in bone growth and differentiation. Mutations in this gene are the cause of brachydactyly type A1, which is characterized by shortening or malformation of the fingers and toes. Mutations in this gene are also the cause of acrocapitofemoral dysplasia. [provided by RefSeq, Nov 2015]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~6.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0007215
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0011907
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0007215
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0011907
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0011907
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007215
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007215
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0011907
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007215
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0011907
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to IHH variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002181.4. 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 | 6 | 59 | 4 | 69 | ||
| missense | 11 | 14 | 172 | 10 | 207 | |
| nonsense | 4 | 3 | 3 | 10 | ||
| start loss | 3 | 1 | 1 | 5 | ||
| frameshift | 12 | 4 | 3 | 19 | ||
| splice donor/acceptor (+/-2bp) | 2 | 1 | 3 | |||
| Total | 30 | 24 | 186 | 69 | 4 | 313 |
Highest pathogenic variant AF is 0.000013164997
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002172.2 | 3 | MANE Select | |
| Ensembl | ENSP00000295731.5 | 3 | MANE Select | |
| Ensembl | ENSP00000785932.1 | 2 | Standard | |
| Ensembl | ENSP00000797512.1 | 1 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| ihhb | Danio rerio | Structure: glioblast (sensu Vertebrata) Quality: increased occurrence abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Proteoglycans in cancer - Homo sapiens (human)
- Hedgehog signaling pathway - Homo sapiens (human)
- HH-Core
- Hedgehog Signaling Pathway
- Hedgehog Signaling Pathway
Biological Process
- skeletal system development
- branching involved in blood vessel morphogenesis
- osteoblast differentiation
- in utero embryonic development
- cell fate specification
Molecular Function
- patched binding
- calcium ion binding
- protein binding
- peptidase activity
Cellular Component
- extracellular space
- plasma membrane
- extracellular matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000295731
- Coding exons
- 3
- Length
- 6048
- Individuals with no LoFs
- 125677
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 5
- Defined
- 125682
- p
- 0.0000199
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.45 | 199 | 266 | 0.749 | 0.0000163 | 2596 |
| Missense (PolyPhen) | 52 | 110.82 | 0.46922 | 1097 | ||
| Synonymous | 0.620 | 109 | 118 | 0.927 | 0.00000738 | 911 |
| Loss of Function | 2.52 | 3 | 12.7 | 0.236 | 5.51e-7 | 135 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000028 | 0.000026 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Intercellular signal essential for a variety of patterning events during development. Binds to the patched (PTC) receptor, which functions in association with smoothened (SMO), to activate the transcription of target genes. Implicated in endochondral ossification: may regulate the balance between growth and ossification of the developing bones. Induces the expression of parathyroid hormone-related protein (PTHRP) (By similarity). {ECO:0000250, ECO:0000269|PubMed:21537345}.;
- Disease
- DISEASE: Brachydactyly A1 (BDA1) [MIM:112500]: A form of brachydactyly. Brachydactyly defines a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. Brachydactyly type A1 is characterized by middle phalanges of all the digits rudimentary or fused with the terminal phalanges. The proximal phalanges of the thumbs and big toes are short. BDA1 inheritance is autosomal dominant. {ECO:0000269|PubMed:11455389, ECO:0000269|PubMed:12384778, ECO:0000269|PubMed:21537345}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Acrocapitofemoral dysplasia (ACFD) [MIM:607778]: An autosomal recessive disorder characterized by short stature of variable severity with postnatal onset. The most constant radiographic abnormalities are observed in the tubular bones of the hands and in the proximal part of the femur. Cone-shaped epiphyses or a similar epiphyseal configuration with premature epimetaphyseal fusion result in shortening of the skeletal components involved. Cone-shaped epiphyses are also present to a variable extent at the shoulders, knees and ankles. {ECO:0000269|PubMed:12632327}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.594
Intolerance Scores
- LoFtool
- 0.0418
- RVIS EVS
- -0.23
- RVIS percentile EVS
- 37.32
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.583
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |