RAI1

protein-coding

retinoic acid induced 1

Gene summary

This gene is located within the Smith-Magenis syndrome region on chromosome 17. It is highly similar to its mouse counterpart and is expressed at high levels mainly in neuronal tissues. The protein encoded by this gene includes a polymorphic polyglutamine tract in the N-terminal domain. Expression of the mouse counterpart in neurons is induced by retinoic acid. This gene is associated with both the severity of the phenotype and the response to medication in schizophrenic patients. [provided by RefSeq, Jul 2008]

Previous symbols:

SMCR

MANE transcript

NM_030665.4

Inheritance

ClinVar variants

P:188U:1072B:1298

Top phenotype

Smith-Magenis syndrome

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr17:17,681,458-17,811,453

External References & Databases

Ensembl (ENSG00000108557)

Transcript & Mutation Effects

hg38 • Region Span ~130.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Smith-Magenis syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008434

Submitter: G2P

Smith-Magenis syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008434

Submitter: Labcorp Genetics (formerly Invitae)

Potocki-Lupski syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0012574

Submitter: Ambry Genetics

Smith-Magenis syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008434

Submitter: ClinGen

*RAI1* was first reported in relation to autosomal dominant Smith-Magenis syndrome in 2003 (Slager et al., PMID: 12652298). A microdeletion overlapping multiple genes in chromosome 17p11.2 was first identified in individuals with Smith-Magenis syndrome, and subsequent studies indicated that haploinsufficiency of *RAI1* within the deleted region is responsible for most of the clinical manifestations. Affected individuals exhibit intellectual disability, delayed speech, dysmorphic facial features, sleep disturbances, and behavioral disorders, including autism. Nine variants (missense, nonsense, and frameshift) that have been reported in nine probands in four publications (PMIDs: 15565467, 15788730, 17041942, 12652298) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. To date, 32 unique variants within *RAI1* have been classified as pathogenic in ClinVar. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by mouse models and patient-derived cells. The experimental evidence collectively shows that *RAI1* is critical for cognitive function (intellectual disability), craniofacial development (dysmorphic facial features), energy homeostasis (obesity), and circadian rhythm (sleep disturbances). In summary, there is definitive evidence supporting the relationship between *RAI1* and autosomal dominant Smith-Magenis syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on September 5, 2018 (SOP Version 5).

Smith-Magenis syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008434

Submitter: Orphanet

Smith-Magenis syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008434

Submitter: Ambry Genetics

Smith-Magenis syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008434

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Smith-Magenis syndromeAD

Manifestation: Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Neurologic

Rationale: The condition may involve sleep disturbances, and treatment with specific agents (eg, tasimelteon) may be beneficial

Refs: 12652298; 15788730; 16845274; 17539903; 21739587; 21897445; 22578325; 34316024

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RAI1 variants in ClinVar

16 Conditions Cataloged

not providedTotal: 2133

RAI1-related disorderTotal: 1048

Inborn genetic diseasesTotal: 524

not specifiedTotal: 242

Smith-Magenis syndromeTotal: 170

Intellectual disabilityTotal: 11

See casesTotal: 3

Developmental disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_030665.4. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar	746 clinvar	16 clinvar	767
missense		8 clinvar	1056 clinvar	423 clinvar	109 clinvar	1596
nonsense	36 clinvar	13 clinvar	4 clinvar			53
start loss			2 clinvar			2
frameshift	84 clinvar	47 clinvar	2 clinvar	3 clinvar	1 clinvar	137
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	120	68	1072	1172	126	2558

Highest pathogenic variant AF is 0.000026392954

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_030665.4	RefSeq	NP_109590.3	4	MANE Select
ENST00000353383.6	Ensembl	ENSP00000323074.4	4	MANE Select
ENST00000395774.1	Ensembl	ENSP00000379120.1	1	Standard
ENST00000471135.2	Ensembl	ENSP00000463607.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

skeletal system development
circadian regulation of gene expression
negative regulation of multicellular organism growth
positive regulation of transcription, DNA-templated
positive regulation of transcription by RNA polymerase II

Molecular Function

DNA-binding transcription factor activity
protein binding
enhancer binding
transcription regulatory region DNA binding
metal ion binding

Cellular Component

nucleus
nucleoplasm
mitochondrion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000353383
Coding exons: 4
Length: 129981
Individuals with no LoFs: 125693
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125698
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.12	1029	1.13e+3	0.907	0.0000747	12193
Missense (PolyPhen)		227	323.88	0.70087		3566
Synonymous	-3.04	610	522	1.17	0.0000376	4106
Loss of Function	6.58	2	54.4	0.0368	0.00000306	629

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000068	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000056	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcriptional regulator of the circadian clock components: CLOCK, ARNTL/BMAL1, ARNTL2/BMAL2, PER1/3, CRY1/2, NR1D1/2 and RORA/C. Positively regulates the transcriptional activity of CLOCK a core component of the circadian clock. Regulates transcription through chromatin remodeling by interacting with other proteins in chromatin as well as proteins in the basic transcriptional machinery. May be important for embryonic and postnatal development. May be involved in neuronal differentiation. {ECO:0000269|PubMed:22578325}.;
Disease: DISEASE: Smith-Magenis syndrome (SMS) [MIM:182290]: Characterized by congenital mental retardation associated with development and growth delays. Affected persons have characteristic behavioral abnormalities, including self-injurious behaviors and sleep disturbance, and distinct craniofacial and skeletal anomalies. {ECO:0000269|PubMed:11404004, ECO:0000269|PubMed:12652298, ECO:0000269|PubMed:24863970}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.117

Intolerance Scores

LoFtool: 0.202
RVIS EVS: -3.68
RVIS percentile EVS: 0.25

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.753

Gene Damage Prediction

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