SUFU

SUFU negative regulator of hedgehog signaling

Basic information

Region (hg38): 10:102503972-102633535

Links

ENSG00000107882 ∙ NCBI:51684 ∙ OMIM:607035 ∙ HGNC:16466 ∙ Uniprot:Q9UMX1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• apraxia (Limited), mode of inheritance: AD
• Joubert syndrome 32 (Limited), mode of inheritance: AR
• medulloblastoma (Strong), mode of inheritance: AD
• Joubert syndrome (Moderate), mode of inheritance: AD
• medulloblastoma (Definitive), mode of inheritance: AD
• ciliopathy (Limited), mode of inheritance: AR
• nevoid basal cell carcinoma syndrome (Definitive), mode of inheritance: AD
• Joubert syndrome 32 (Strong), mode of inheritance: AR
• medulloblastoma (Strong), mode of inheritance: AD
• nevoid basal cell carcinoma syndrome (Strong), mode of inheritance: AD
• nevoid basal cell carcinoma syndrome (Supportive), mode of inheritance: AD
• Joubert syndrome (Supportive), mode of inheritance: AR
• neurodevelopmental disorder (Strong), mode of inheritance: AD
• Joubert syndrome 32 (Strong), mode of inheritance: AR
• basal cell nevus syndrome 2 (Strong), mode of inheritance: AD
• Joubert syndrome 32 (Strong), mode of inheritance: AR
• ocular motor apraxia, Cogan type (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Medulloblastoma; Basal cell nevus syndrome 2	AD	Oncologic	Individuals are at risk for a number of types of malignancies (including medulloblastoma), and surveillance may allow early diagnosis and treatment (including with molecular therapies that target the Hedgehog signaling pathway), potentially reducing morbidity and mortality; Avoidance of agents such as radiation therapy is indicated	Craniofacial; Dermatologic; Musculoskeletal; Neurologic; Oncologic	12068298; 19533801; 19833601; 21188540; 22670903; 22670904; 28965847; 36825822

ClinVar

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

• Medulloblastoma (1281 variants)
• Gorlin_syndrome (1277 variants)
• Hereditary_cancer-predisposing_syndrome (1043 variants)
• not_provided (241 variants)
• Familial_meningioma (99 variants)
• not_specified (74 variants)
• Joubert_syndrome_32 (44 variants)
• Basal_cell_nevus_syndrome_2 (44 variants)
• SUFU-related_disorder (29 variants)
• Basal_cell_nevus_syndrome_1 (3 variants)
• Neurodevelopmental_disorder (1 variants)
• Congenital_fibrosarcoma (1 variants)
• See_cases (1 variants)
• Prostate_cancer (1 variants)
• SUFU-related_ocular_motor_apraxia (1 variants)
• B_Lymphoblastic_Leukemia/Lymphoma,_Not_Otherwise_Specified (1 variants)
• Microform_holoprosencephaly (1 variants)
• Oculomotor_apraxia_-_Cogan_type (1 variants)
• Oculomotor_apraxia (1 variants)
• Craniopharyngioma (1 variants)
• Meningioma (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SUFU gene is commonly pathogenic or not. These statistics are base on transcript: NM_000016169.4. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			8	436	3	447
missense	1	3	790	65		859
nonsense	24	4	2			30
start loss		1	1			2
frameshift	56	13	4			73
splice donor/acceptor (+/-2bp)	2	25	4			31
Total	83	46	809	501	3

Highest pathogenic variant AF is 0.000043044634

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SUFU	protein_coding	protein_coding	ENST00000369902	12	129549

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
		124184	0	1	124185	0.00000403

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.93	194	286	0.678	0.0000179	3158
Missense in Polyphen		47	107.27	0.43813		1250
Synonymous	0.716	108	118	0.916	0.00000780	967
Loss of Function	4.80	0	26.9	0.00	0.00000146	288

LoF frequencies by population

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

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Negative regulator in the hedgehog/smoothened signaling pathway. Down-regulates GLI1-mediated transactivation of target genes (PubMed:15367681, PubMed:24311597, PubMed:24217340). Down- regulates GLI2-mediated transactivation of target genes (PubMed:24311597, PubMed:24217340). Part of a corepressor complex that acts on DNA-bound GLI1. May also act by linking GLI1 to BTRC and thereby targeting GLI1 to degradation by the proteasome. Sequesters GLI1, GLI2 and GLI3 in the cytoplasm, this effect is overcome by binding of STK36 to both SUFU and a GLI protein (PubMed:10806483, PubMed:24217340). Negative regulator of beta- catenin signaling. Regulates the formation of either the repressor form (GLI3R) or the activator form (GLI3A) of the full-length form of GLI3 (GLI3FL). GLI3FL is complexed with SUFU in the cytoplasm and is maintained in a neutral state. Without the Hh signal, the SUFU-GLI3 complex is recruited to cilia, leading to the efficient processing of GLI3FL into GLI3R. When Hh signaling is initiated, SUFU dissociates from GLI3FL and the latter translocates to the nucleus, where it is phosphorylated, destabilized, and converted to a transcriptional activator (GLI3A). Required for normal embryonic development. Required for the proper formation of hair follicles and the control of epidermal differentiation (By similarity). {ECO:0000250|UniProtKB:Q9Z0P7, ECO:0000269|PubMed:10559945, ECO:0000269|PubMed:10564661, ECO:0000269|PubMed:10806483, ECO:0000269|PubMed:12068298, ECO:0000269|PubMed:12975309, ECO:0000269|PubMed:15367681, ECO:0000269|PubMed:22365972, ECO:0000269|PubMed:24217340, ECO:0000269|PubMed:24311597, ECO:0000269|PubMed:28965847}.
• Disease: DISEASE: Joubert syndrome 32 (JBTS32) [MIM:617757]: A form of Joubert syndrome, a disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy, renal disease, liver fibrosis, and polydactyly. JBTS32 inheritance is autosomal recessive. {ECO:0000269|PubMed:28965847}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Basal cell carcinoma - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Hedgehog signaling pathway - Homo sapiens (human);HH-Core;Hedgehog Signaling Pathway;Hedgehog Signaling Pathway;Signal Transduction;GLI3 is processed to GLI3R by the proteasome;Hedgehog;Degradation of GLI2 by the proteasome;Degradation of GLI1 by the proteasome;Hedgehog ,off, state;Hedgehog ,on, state;Signaling by Hedgehog;Hedgehog signaling events mediated by Gli proteins (Consensus)

Recessive Scores

• pRec: 0.194

Intolerance Scores

• rvis_EVS: -0.58
• rvis_percentile_EVS: 18.59

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.999

Gene Damage Prediction

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

Zebrafish Information Network

• Gene name: sufu
• Affected structure: thrombocyte
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;skeletal system development;neural tube closure;heart looping;ventricular septum development;regulation of transcription, DNA-templated;proteolysis;signal transduction;multicellular organism development;smoothened signaling pathway involved in ventral spinal cord interneuron specification;smoothened signaling pathway involved in spinal cord motor neuron cell fate specification;aorta development;negative regulation of protein import into nucleus;cytoplasmic sequestering of transcription factor;negative regulation of DNA-binding transcription factor activity;skin development;negative regulation of osteoblast differentiation;negative regulation of smoothened signaling pathway;coronary vasculature development;negative regulation of smoothened signaling pathway involved in dorsal/ventral neural tube patterning;negative regulation of ubiquitin-dependent protein catabolic process
• Cellular component: nucleus;cytoplasm;cytosol;ciliary tip;ciliary base
• Molecular function: transcription corepressor activity;protein binding;beta-catenin binding;transcription factor binding;protein kinase binding