IHH

Indian hedgehog signaling molecule, the group of Hedgehog signaling molecule family|MicroRNA protein coding host genes

Basic information

Region (hg38): 2:219054424-219060921

Links

ENSG00000163501 ∙ NCBI:3549 ∙ OMIM:600726 ∙ HGNC:5956 ∙ Uniprot:Q14623 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• brachydactyly type A1 (Definitive), mode of inheritance: AD
• acrocapitofemoral dysplasia (Definitive), mode of inheritance: AR
• acrocapitofemoral dysplasia (Supportive), mode of inheritance: AR
• brachydactyly type A1 (Supportive), mode of inheritance: AD
• acrocapitofemoral dysplasia (Strong), mode of inheritance: AR
• brachydactyly type A1 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Acrocapitofemoral dysplasia; Brachydactyly, type A1	AD/AR	General	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	Musculoskeletal	8592325; 11455389; 12384778; 12525541; 15886999; 16871364; 17486609; 18629882; 22406540

ClinVar

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

• not provided (13 variants)
• Brachydactyly type A1 (2 variants)
• Brachydactyly type A1A (2 variants)
• Acrocapitofemoral dysplasia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the IHH 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			7	39	10	56
missense	4	4	101	1	2	112
nonsense	4		1			5
start loss	2	1	1			4
frameshift	4	2	3			9
inframe indel		2	3			5
splice donor/acceptor (+/-2bp)		1	1			2
splice region			1	1		2
non coding			15	9	11	35
Total	14	10	132	49	23

Highest pathogenic variant AF is 0.0000132

Variants in IHH

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

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

Position	Type	Phenotype	Significance	ClinVar
2-219054583-C-CG		Brachydactyly	Uncertain significance (Jun 14, 2016)
2-219054611-C-T		Brachydactyly type A1	Uncertain significance (Jan 12, 2018)
2-219054784-C-T		Brachydactyly type A1	Uncertain significance (Jan 12, 2018)
2-219054810-C-T		Brachydactyly type A1	Uncertain significance (Jan 12, 2018)
2-219054839-C-T		Brachydactyly type A1	Uncertain significance (Jan 13, 2018)
2-219054894-G-A		Brachydactyly type A1	Uncertain significance (Jan 13, 2018)
2-219054907-A-G		Brachydactyly type A1	Uncertain significance (Jan 12, 2018)
2-219054940-T-A		Brachydactyly type A1	Uncertain significance (Mar 02, 2018)
2-219054959-G-T		Brachydactyly type A1	Benign (Jan 13, 2018)
2-219054961-C-G		Brachydactyly type A1	Uncertain significance (Jan 12, 2018)
2-219054990-C-T		Brachydactyly type A1	Uncertain significance (Jan 12, 2018)
2-219055008-C-T		Brachydactyly type A1	Uncertain significance (Jan 13, 2018)
2-219055032-G-C		Brachydactyly type A1	Benign (Apr 10, 2019)
2-219055124-T-A		Brachydactyly type A1	Benign (Jan 12, 2018)
2-219055174-C-T		Brachydactyly type A1	Uncertain significance (Jan 13, 2018)
2-219055182-C-A		Brachydactyly type A1	Benign (Nov 12, 2018)
2-219055194-C-T		Brachydactyly type A1	Benign (Jan 13, 2018)
2-219055217-G-A		Inborn genetic diseases	Uncertain significance (Jul 25, 2023)
2-219055221-C-T		Brachydactyly type A1	Conflicting classifications of pathogenicity (Jan 08, 2024)
2-219055222-G-A		Brachydactyly type A1	Likely benign (Jan 18, 2024)
2-219055226-A-T			Uncertain significance (Nov 16, 2023)
2-219055230-C-T		Inborn genetic diseases	Uncertain significance (Mar 06, 2023)
2-219055242-A-G		Inborn genetic diseases	Uncertain significance (Oct 12, 2021)
2-219055249-C-G		Inborn genetic diseases	Uncertain significance (May 10, 2024)
2-219055266-G-C		Inborn genetic diseases	Uncertain significance (Sep 25, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
IHH	protein_coding	protein_coding	ENST00000295731	3	6048

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.314	0.683	125677	0	5	125682	0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.45	199	266	0.749	0.0000163	2596
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000290	0.0000290
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000463	0.0000462
European (Non-Finnish)	0.0000280	0.0000264
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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.
• Pathway: Proteoglycans in cancer - Homo sapiens (human);Hedgehog signaling pathway - Homo sapiens (human);HH-Core;Hedgehog Signaling Pathway;Hedgehog Signaling Pathway;Endochondral Ossification;Signaling by GPCR;RUNX2 regulates chondrocyte maturation;RUNX2 regulates bone development;Transcriptional regulation by RUNX2;Signal Transduction;Gene expression (Transcription);Generic Transcription Pathway;Hedgehog;GPCR signaling-G alpha q;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;RNA Polymerase II Transcription;Hedgehog;Release of Hh-Np from the secreting cell;Hedgehog ligand biogenesis;Class B/2 (Secretin family receptors);GPCR ligand binding;GPCR signaling-G alpha s Epac and ERK;Ligand-receptor interactions;GPCR signaling-G alpha s PKA and ERK;Hedgehog ,on, state;Signaling by Hedgehog;GPCR signaling-G alpha i;Signaling events mediated by the Hedgehog family (Consensus)

Recessive Scores

• pRec: 0.594

Intolerance Scores

• loftool: 0.0418
• rvis_EVS: -0.23
• rvis_percentile_EVS: 37.32

Haploinsufficiency Scores

• pHI: 0.685
• hipred: Y
• hipred_score: 0.675
• ghis: 0.437

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.583

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ihh
• Phenotype: cellular phenotype; muscle phenotype; craniofacial phenotype; growth/size/body region phenotype; endocrine/exocrine gland phenotype; respiratory system phenotype; skeleton phenotype; digestive/alimentary 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; 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); 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); embryo phenotype

Zebrafish Information Network

• Gene name: ihhb
• Affected structure: glioblast (sensu Vertebrata)
• Phenotype tag: abnormal
• Phenotype quality: increased occurrence

Gene ontology

• Biological process: skeletal system development;branching involved in blood vessel morphogenesis;osteoblast differentiation;in utero embryonic development;cell fate specification;heart looping;positive regulation of mesenchymal cell proliferation;epithelial cell morphogenesis;retinal pigment epithelium development;chondrocyte differentiation involved in endochondral bone morphogenesis;proteoglycan metabolic process;smoothened signaling pathway;cell-cell signaling;response to mechanical stimulus;embryonic pattern specification;intein-mediated protein splicing;vitelline membrane formation;pancreas development;response to estradiol;positive regulation of collagen biosynthetic process;negative regulation of T cell differentiation in thymus;negative regulation of immature T cell proliferation in thymus;positive regulation of T cell differentiation in thymus;multicellular organism growth;chondrocyte proliferation;regulation of growth;embryonic digit morphogenesis;negative regulation of apoptotic process;bone resorption;positive regulation of smoothened signaling pathway;positive regulation of transcription by RNA polymerase II;positive regulation of alpha-beta T cell differentiation;negative regulation of alpha-beta T cell differentiation;negative regulation of eye pigmentation;cell maturation;embryonic digestive tract morphogenesis;embryonic camera-type eye morphogenesis;neuron development;smooth muscle tissue development;positive regulation of epithelial cell proliferation;maternal process involved in female pregnancy;camera-type eye photoreceptor cell fate commitment;head morphogenesis;somite development;embryonic skeletal joint development;epithelial cell-cell adhesion;liver regeneration
• Cellular component: extracellular space;plasma membrane;extracellular matrix
• Molecular function: patched binding;calcium ion binding;protein binding;peptidase activity