GeneBe

REST

protein-coding

RE1 silencing transcription factor

Gene summary

This gene was initially identified as a transcriptional repressor that represses neuronal genes in non-neuronal tissues. However, depending on the cellular context, this gene can act as either an oncogene or a tumor suppressor. The encoded protein is a member of the Kruppel-type zinc finger transcription factor family. It represses transcription by binding a DNA sequence element called the neuron-restrictive silencer element. The protein is also found in undifferentiated neuronal progenitor cells and it is thought that this repressor may act as a master negative regulator of neurogenesis. Alternatively spliced transcript variants have been described. [provided by RefSeq, May 2018]

Previous symbols:
  • DFNA27

MANE transcript

NM_005612.5

Inheritance

AD

ClinVar variants

P:29U:471B:250

Top phenotype

Wilms tumor 6

gnomAD constraint

pLI —, LoF o/e 0.12

Max pathogenic AF

—

Genomic locus

chr4:56,907,876-56,966,808

External References & Databases

Ensembl (ENSG00000084093)NCBI Gene (5978)OMIM (600571)HGNC:9966GenCCUniProt (Q13127)AlphaFoldClinVar (REST)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~58.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

fibromatosis, gingival, 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033493

Submitter: PanelApp Australia

autosomal dominant nonsyndromic hearing loss 27MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0012902

Submitter: PanelApp Australia

Wilms tumor 6LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014779

Submitter: Ambry Genetics

Wilms tumor 6STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014779

Submitter: Labcorp Genetics (formerly Invitae)

fibromatosis, gingival, 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033493

Submitter: Labcorp Genetics (formerly Invitae)

fibromatosis, gingival, 5MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0033493

Submitter: Ambry Genetics

Wilms tumor 6MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014779

Submitter: G2P

autosomal dominant nonsyndromic hearing loss 27LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012902

Submitter: Ambry Genetics

hereditary gingival fibromatosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016070

Submitter: Orphanet

Wilms tumor 6STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014779

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Wilms tumor 6AD

Manifestation: Audiologic/Otolaryngologic; Dental; Oncologic

Intervention: Oncologic

Rationale: Surveillance and early detection of and treatment for Wilms tumor may decrease morbidity and mortality

Refs: 18279434; 26551668; 28686854; 29961578Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to REST variants in ClinVar

10 Conditions Cataloged
not providedTotal: 669
Inborn genetic diseasesTotal: 133
REST-related disorderTotal: 97
not specifiedTotal: 59
Wilms tumor 6Total: 58
Fibromatosis, gingival, 5Total: 50
Autosomal dominant nonsyndromic hearing loss 27Total: 43
Fibromatosis, gingival, 1Total: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005612.5. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
195
clinvar
1
clinvar
 197
missense
1
clinvar
456
clinvar
47
clinvar
6
clinvar
 510
nonsense
6
clinvar
4
clinvar
5
clinvar
 15
start loss
0
frameshift
8
clinvar
10
clinvar
6
clinvar
 24
splice donor/acceptor (+/-2bp)
3
clinvar
1
clinvar
 4
Total14154712437750

Highest pathogenic variant AF is 0.0000037176565

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 40 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_005612.5RefSeqNP_005603.33MANE Select
ENST00000309042.12EnsemblENSP00000311816.73MANE Select
NM_001193508.2RefSeqNP_001180437.13Standard
NM_001363453.3RefSeqNP_001350382.13Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
restDanio rerio

Structure: primary motor neuron

Quality: structure

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • 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

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

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

Cellular Component

  • nucleus
  • nucleoplasm
  • cytoplasm
  • cytosol
  • transcriptional repressor complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000309042
Coding exons
3
Length
27936
Individuals with no LoFs
125733
Homozygous LoFs
0
Heterozygous LoFs
15
Defined
125748
p
0.0000596
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.7815315840.9090.00002937252
Missense (PolyPhen)120211.620.567062697
Synonymous-1.522332051.130.00001052075
Loss of Function4.59432.00.1250.00000176452

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American0.0000580.000058rare
Ashkenazi Jewish00.0absent
East Asian0.000600.00033rare
Finnish0.0000460.000046rare
European (Non-Finnish)0.0000450.000044rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec
0.396

Intolerance Scores

LoFtool
0.483
RVIS EVS
2.07
RVIS percentile EVS
97.81

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
1.00

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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