REST

RE1 silencing transcription factor

Basic information

Region (hg38): 4:56907875-56966808

Previous symbols: [ "DFNA27" ]

Links

ENSG00000084093 ∙ NCBI:5978 ∙ OMIM:600571 ∙ HGNC:9966 ∙ Uniprot:Q13127 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hereditary gingival fibromatosis (Supportive), mode of inheritance: AD
• autosomal dominant nonsyndromic hearing loss 27 (Limited), mode of inheritance: AD
• Wilms tumor 6 (Limited), mode of inheritance: AD
• fibromatosis, gingival, 5 (Moderate), mode of inheritance: AD
• fibromatosis, gingival, 5 (Strong), mode of inheritance: AD
• Wilms tumor 6 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Wilms tumor 6	AD	Oncologic	Surveillance and early detection of and treatment for Wilms tumor may decrease morbidity and mortality	Audiologic/Otolaryngologic; Dental; Oncologic	18279434; 26551668; 28686854; 29961578

ClinVar

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

• not provided (444 variants)
• Inborn genetic diseases (50 variants)
• REST-related condition (15 variants)
• Wilms tumor 6 (9 variants)
• Fibromatosis, gingival, 5 (6 variants)
• Fibromatosis, gingival, 1 (3 variants)
• not specified (2 variants)
• Wilms tumor 6;Autosomal dominant nonsyndromic hearing loss 27;Fibromatosis, gingival, 5 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the REST 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	109	16	128
missense			262	24	11	297
nonsense	3	2	2			7
start loss						0
frameshift	6	4	4			14
inframe indel			14	1	1	16
splice donor/acceptor (+/-2bp)						0
splice region			1	2		3
non coding			8	7	10	25
Total	9	6	293	141	38

Highest pathogenic variant AF is 0.00000657

Variants in REST

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

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

Position	Type	Phenotype	Significance	ClinVar
4-56910349-G-A			Benign (Mar 27, 2019)
4-56910642-G-A			Uncertain significance (Nov 25, 2020)
4-56910680-G-A			Likely benign (Dec 11, 2023)
4-56910681-C-G			Uncertain significance (Oct 02, 2021)
4-56910690-A-C		Inborn genetic diseases	Uncertain significance (Apr 22, 2022)
4-56910690-A-G			Uncertain significance (Apr 06, 2023)
4-56910700-A-G			Uncertain significance (Jul 17, 2023)
4-56910706-G-A		REST-related disorder • Inborn genetic diseases	Uncertain significance (Jan 09, 2024)
4-56910708-A-G			Uncertain significance (Oct 22, 2023)
4-56910713-C-T			Likely benign (Jun 08, 2022)
4-56910723-G-A			Uncertain significance (Dec 10, 2023)
4-56910725-C-A		Inborn genetic diseases	Uncertain significance (Dec 20, 2023)
4-56910726-A-G			Uncertain significance (Jan 07, 2024)
4-56910727-T-C			Uncertain significance (Dec 21, 2023)
4-56910728-G-T			Uncertain significance (Nov 19, 2021)
4-56910730-A-G			Uncertain significance (Nov 05, 2020)
4-56910734-C-T			Likely benign (Jan 09, 2023)
4-56910733-A-ACTT			Uncertain significance (Mar 22, 2021)
4-56910739-A-G			Uncertain significance (Jan 07, 2024)
4-56910749-C-G			Likely benign (Nov 01, 2022)
4-56910762-G-A			Uncertain significance (Jul 15, 2021)
4-56910767-A-G			Likely benign (Dec 15, 2022)
4-56910769-C-G		REST-related disorder	Uncertain significance (Dec 06, 2023)
4-56910774-C-G		Inborn genetic diseases	Uncertain significance (Jun 29, 2022)
4-56910785-G-A			Uncertain significance (Jan 12, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
REST	protein_coding	protein_coding	ENST00000309042	3	27936

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.992	0.00814	125733	0	15	125748	0.0000596

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.781	531	584	0.909	0.0000293	7252
Missense in Polyphen		120	211.62	0.56706		2697
Synonymous	-1.52	233	205	1.13	0.0000105	2075
Loss of Function	4.59	4	32.0	0.125	0.00000176	452

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000119	0.000119
Ashkenazi Jewish	0.00	0.00
East Asian	0.000603	0.000326
Finnish	0.0000464	0.0000462
European (Non-Finnish)	0.0000445	0.0000439
Middle Eastern	0.000603	0.000326
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transcriptional repressor which binds neuron-restrictive silencer element (NRSE) and represses neuronal gene transcription in non-neuronal cells. Restricts the expression of neuronal genes by associating with two distinct corepressors, mSin3 and CoREST, which in turn recruit histone deacetylase to the promoters of REST-regulated genes. Mediates repression by recruiting the BHC complex at RE1/NRSE sites which acts by deacetylating and demethylating specific sites on histones, thereby acting as a chromatin modifier. Transcriptional repression by REST-CDYL via the recruitment of histone methyltransferase EHMT2 may be important in transformation suppression. Key repressor of gene expression in hypoxia; represses genes in hypoxia by direct binding to an RE1/NRSE site on their promoter regions (PubMed:27531581). Negatively regulates the expression of SRRM3 in breast cancer cell lines (PubMed:26053433). Represses the expression of SRRM4 in non-neural cells to prevent the activation of neural specific splicing events (By similarity). Acts as a regulator of osteoblast differentiation (By similarity). {ECO:0000250|UniProtKB:Q8VIG1, ECO:0000269|PubMed:12399542, ECO:0000269|PubMed:19061646, ECO:0000269|PubMed:26053433, ECO:0000269|PubMed:26551668, ECO:0000269|PubMed:27531581, ECO:0000269|PubMed:7697725, ECO:0000269|PubMed:7871435, ECO:0000269|PubMed:8568247}.
• Disease: DISEASE: Fibromatosis, gingival, 5 (GINGF5) [MIM:617626]: An autosomal dominant form of hereditary gingival fibromatosis, a rare condition characterized by a slow, progressive overgrowth of the gingiva. The excess gingival tissue can cover part of or the entire crown, and can result in diastemas, teeth displacement, or retention of primary or impacted teeth. {ECO:0000269|PubMed:28686854}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Huntington,s disease - Homo sapiens (human);Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human);MECP2 and Associated Rett Syndrome;Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways;Signal Transduction;HDACs deacetylate histones;Chromatin modifying enzymes;Regulation of PTEN gene transcription;PTEN Regulation;PIP3 activates AKT signaling;Chromatin organization;Intracellular signaling by second messengers (Consensus)

Recessive Scores

• pRec: 0.396

Intolerance Scores

• loftool: 0.483
• rvis_EVS: 2.07
• rvis_percentile_EVS: 97.81

Haploinsufficiency Scores

• pHI: 0.174
• hipred: Y
• hipred_score: 0.633
• ghis: 0.420

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 1.00

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Rest
• Phenotype: cellular phenotype; pigmentation phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands 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); reproductive system phenotype; growth/size/body region phenotype; hematopoietic system 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); vision/eye phenotype; limbs/digits/tail 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); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype

Zebrafish Information Network

• Gene name: rest
• Affected structure: primary motor neuron
• Phenotype tag: abnormal
• Phenotype quality: structure

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;regulation of alternative mRNA splicing, via spliceosome;response to hypoxia;hematopoietic progenitor cell differentiation;regulation of transcription, DNA-templated;negative regulation of cell population proliferation;regulation of gene expression;negative regulation of gene expression;negative regulation of aldosterone biosynthetic process;cellular response to drug;positive regulation of apoptotic process;positive regulation of cysteine-type endopeptidase activity involved in apoptotic process;negative regulation by host of viral transcription;negative regulation of neuron differentiation;positive regulation of neuron differentiation;regulation of osteoblast differentiation;negative regulation of transcription, DNA-templated;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;negative regulation of calcium ion-dependent exocytosis;negative regulation of insulin secretion;negative regulation of neurogenesis;cardiac muscle cell myoblast differentiation;histone H4 deacetylation;cellular response to electrical stimulus;cellular response to glucocorticoid stimulus;potassium ion transmembrane transport;negative regulation of cortisol biosynthetic process;negative regulation of dense core granule biogenesis;negative regulation of mesenchymal stem cell differentiation;negative regulation of amniotic stem cell differentiation
• Cellular component: nucleus;nucleoplasm;cytoplasm;cytosol;transcriptional repressor complex;histone methyltransferase complex
• Molecular function: RNA polymerase II proximal promoter sequence-specific DNA binding;RNA polymerase II core promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription repressor activity, RNA polymerase II-specific;DNA-binding transcription activator activity, RNA polymerase II-specific;chromatin binding;DNA-binding transcription factor activity;histone deacetylase activity;protein binding;transcription factor binding;outward rectifier potassium channel activity;transcription regulatory region DNA binding;metal ion binding