SMO

smoothened, frizzled class receptor, the group of G protein-coupled receptors, Class F frizzled

Basic information

Region (hg38): 7:129188632-129213545

Previous symbols: [ "SMOH" ]

Links

ENSG00000128602 ∙ NCBI:6608 ∙ OMIM:601500 ∙ HGNC:11119 ∙ Uniprot:Q99835 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Curry-Jones syndrome (Definitive), mode of inheritance: Somatic mosaicism
• Curry-Jones syndrome (Strong), mode of inheritance: AD
• Hirschsprung disease (Supportive), mode of inheritance: AD
• medulloblastoma (Limited), mode of inheritance: AD
• congenital hypothalamic hamartoma syndrome (Moderate), mode of inheritance: AR
• Curry-Jones syndrome (Definitive), mode of inheritance: AD
• congenital hypothalamic hamartoma syndrome (Moderate), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Pallister-Hall like syndrome	AR	Cardiovascular	The condition can involve congenital cardiac anomalies, and awareness may allow early management; Interventions related to endocrine abnormalities may be beneficial; Surgical interventions related to hypothalamic hamartoma may be indicated	Cardiovascular; Endocrine; Musculoskeletal; Neurologic	27236920; 30497210; 32413283
Somatic variants can result in Curry-Jones syndrome

ClinVar

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

• not provided (82 variants)
• Inborn genetic diseases (26 variants)
• not specified (19 variants)
• Hamartoma of hypothalamus (13 variants)
• Curry-Jones syndrome (5 variants)
• SMO-related condition (4 variants)
• Hamartoma of hypothalamus;Basal cell carcinoma, susceptibility to, 1;Curry-Jones syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SMO 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			3	15	5	23
missense	2	2	45	4	3	56
nonsense			1			1
start loss						0
frameshift			1			1
inframe indel					1	1
splice donor/acceptor (+/-2bp)						0
splice region			2			2
non coding			1	19	17	37
Total	2	2	51	38	26

Highest pathogenic variant AF is 0.00000657

Variants in SMO

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

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

Position	Type	Phenotype	Significance	ClinVar
7-129188737-G-T			Likely benign (Feb 24, 2019)
7-129189117-G-T			Likely benign (Apr 09, 2019)
7-129189164-C-T		Inborn genetic diseases	Uncertain significance (Jan 24, 2024)
7-129189165-G-C		Inborn genetic diseases	Uncertain significance (Oct 26, 2022)
7-129189194-C-G		See cases	Benign (Jul 31, 2022)
7-129189198-G-GGCT		SMO-related disorder	Benign/Likely benign (Mar 09, 2022)
7-129189199-G-GCTC			Uncertain significance (-)
7-129189225-A-G			Benign (Dec 31, 2019)
7-129189250-C-G		not specified	not provided (Sep 19, 2013)
7-129189263-G-T		Inborn genetic diseases	Uncertain significance (Apr 07, 2023)
7-129189311-G-A		not specified	Uncertain significance (Aug 19, 2020)
7-129189324-C-T		Hamartoma of hypothalamus	Uncertain significance (Sep 22, 2023)
7-129189327-C-A		Inborn genetic diseases	Uncertain significance (Jul 05, 2023)
7-129189343-C-A			Uncertain significance (Jun 20, 2021)
7-129189357-C-A		Inborn genetic diseases	Uncertain significance (Apr 11, 2023)
7-129189619-G-A			Likely benign (Jun 17, 2021)
7-129203141-G-T			Likely benign (Feb 28, 2019)
7-129203328-C-T			Benign (Jan 10, 2019)
7-129203436-C-T			Benign/Likely benign (Feb 01, 2024)
7-129203437-G-A			Uncertain significance (Apr 03, 2023)
7-129203444-T-C			Uncertain significance (Sep 14, 2021)
7-129203482-C-T		SMO-related disorder	Uncertain significance (Jan 26, 2023)
7-129203555-G-A		not specified	Benign (Dec 31, 2019)
7-129203564-C-G		Inborn genetic diseases	Uncertain significance (Jan 23, 2024)
7-129203568-C-T		SMO-related disorder	Likely benign (Feb 20, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SMO	protein_coding	protein_coding	ENST00000249373	12	24674

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
4.28e-7	1.00	125711	0	37	125748	0.000147

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.90	345	459	0.751	0.0000287	5019
Missense in Polyphen		78	130.22	0.59899		1386
Synonymous	0.0952	183	185	0.991	0.0000115	1657
Loss of Function	3.08	17	37.3	0.456	0.00000223	344

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000352	0.000352
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.0000926	0.0000924
European (Non-Finnish)	0.000163	0.000158
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000980	0.0000980
Other	0.000334	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: G protein-coupled receptor that probably associates with the patched protein (PTCH) to transduce the hedgehog's proteins signal. Binding of sonic hedgehog (SHH) to its receptor patched is thought to prevent normal inhibition by patched of smoothened (SMO). Required for the accumulation of KIF7, GLI2 and GLI3 in the cilia (PubMed:19592253). Interacts with DLG5 at the ciliary base to induce the accumulation of KIF7 and GLI2 at the ciliary tip for GLI2 activation (By similarity). {ECO:0000250|UniProtKB:P56726, ECO:0000269|PubMed:19592253}.
• Disease: DISEASE: Curry-Jones syndrome (CRJS) [MIM:601707]: A multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas. {ECO:0000269|PubMed:24859340, ECO:0000269|PubMed:27236920}. Note=The disease is caused by mutations affecting the gene represented in this entry. 8 individuals have been identified with the disease-causing mutation Phe-412 and all were mosaic. The mutation could not be reliably detected in blood, greatest success rates were obtained with affected tissues obtained by invasive procedures. It is thought that the mutation has arisen postzygotically early during embryonic development (PubMed:27236920). This mutation has also been identified in ameloblastoma, medulloblastoma, meningioma, and basal cell carcinoma, and has been reported as the oncogenic driver in some of these tumors (PubMed:24859340). {ECO:0000269|PubMed:24859340, ECO:0000269|PubMed:27236920}.
• Pathway: Axon guidance - Homo sapiens (human);Basal cell carcinoma - Homo sapiens (human);Proteoglycans in cancer - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Hedgehog signaling pathway - Homo sapiens (human);HH-Core;GPCRs, Other;Hair Follicle Development- Induction (Part 1 of 3);Tumor suppressor activity of SMARCB1;Hedgehog Signaling Pathway;Hedgehog Signaling Pathway;Signaling by GPCR;Signal Transduction;Hedgehog;GPCR signaling-G alpha q;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;Activation of SMO;Hedgehog;Class B/2 (Secretin family receptors);GPCR ligand binding;GPCR signaling-G alpha s Epac and ERK;GPCR signaling-G alpha s PKA and ERK;Hedgehog ,on, state;Signaling by Hedgehog;GPCR signaling-G alpha i;BBSome-mediated cargo-targeting to cilium;Hedgehog signaling events mediated by Gli proteins;Signaling events mediated by the Hedgehog family;Cargo trafficking to the periciliary membrane;Cilium Assembly;Organelle biogenesis and maintenance (Consensus)

Recessive Scores

• pRec: 0.412

Intolerance Scores

• loftool: 0.242
• rvis_EVS: -0.57
• rvis_percentile_EVS: 18.9

Haploinsufficiency Scores

• pHI: 0.608
• hipred: Y
• hipred_score: 0.650
• ghis: 0.522

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.963

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Smo
• 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); normal 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); respiratory system phenotype; embryo phenotype; skeleton phenotype; vision/eye phenotype; digestive/alimentary phenotype; muscle phenotype; limbs/digits/tail 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); growth/size/body region phenotype; homeostasis/metabolism phenotype; cellular phenotype; craniofacial phenotype

Zebrafish Information Network

• Gene name: smo
• Affected structure: retinal ganglion cell
• Phenotype tag: abnormal
• Phenotype quality: process quality

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;vasculogenesis;osteoblast differentiation;in utero embryonic development;cell fate specification;neural crest cell migration;heart looping;positive regulation of neuroblast proliferation;positive regulation of mesenchymal cell proliferation;determination of left/right asymmetry in lateral mesoderm;type B pancreatic cell development;G protein-coupled receptor signaling pathway;smoothened signaling pathway;positive regulation of hh target transcription factor activity;ventral midline determination;central nervous system development;midgut development;anterior/posterior pattern specification;positive regulation of gene expression;negative regulation of gene expression;dentate gyrus development;cerebellar cortex morphogenesis;thalamus development;dorsal/ventral neural tube patterning;smoothened signaling pathway involved in ventral spinal cord patterning;smoothened signaling pathway involved in regulation of cerebellar granule cell precursor cell proliferation;central nervous system neuron differentiation;cerebral cortex development;negative regulation of epithelial cell differentiation;hair follicle morphogenesis;protein localization to nucleus;multicellular organism growth;positive regulation of multicellular organism growth;positive regulation of protein import into nucleus;odontogenesis of dentin-containing tooth;negative regulation of apoptotic process;negative regulation of DNA binding;positive regulation of smoothened signaling pathway;positive regulation of transcription by RNA polymerase II;positive regulation of organ growth;astrocyte activation;skeletal muscle fiber development;forebrain morphogenesis;homeostasis of number of cells within a tissue;positive regulation of epithelial cell proliferation;protein stabilization;myoblast migration;negative regulation of hair follicle development;detection of cell density by contact stimulus involved in contact inhibition;atrial septum morphogenesis;mammary gland epithelial cell differentiation;epithelial-mesenchymal cell signaling;somite development;pancreas morphogenesis;left/right axis specification;cellular response to cholesterol;commissural neuron axon guidance;renal system development;mesenchymal to epithelial transition involved in metanephric renal vesicle formation;positive regulation of branching involved in ureteric bud morphogenesis;regulation of stem cell population maintenance;regulation of heart morphogenesis
• Cellular component: Golgi apparatus;plasma membrane;caveola;cilium;integral component of membrane;dendrite;endocytic vesicle membrane;intracellular membrane-bounded organelle;ciliary membrane;extracellular exosome;ciliary tip
• Molecular function: G protein-coupled receptor activity;patched binding;protein binding;drug binding