RHEB

protein-coding

Ras homolog, mTORC1 binding, the group of RAS type GTPase family

Gene summary

This gene is a member of the small GTPase superfamily and encodes a lipid-anchored, cell membrane protein with five repeats of the RAS-related GTP-binding region. This protein is vital in regulation of growth and cell cycle progression due to its role in the insulin/TOR/S6K signaling pathway. The protein has GTPase activity and shuttles between a GDP-bound form and a GTP-bound form, and farnesylation of the protein is required for this activity. Three pseudogenes have been mapped, two on chromosome 10 and one on chromosome 22. [provided by RefSeq, Jul 2008]

Previous symbols:

RHEB2

MANE transcript

NM_005614.4

Inheritance

ClinVar variants

P:8U:23B:1

Top phenotype

Isolated focal cortical dysplasia type II

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr7:151,466,012-151,520,120

External References & Databases

Ensembl (ENSG00000106615)

Transcript & Mutation Effects

hg38 • Region Span ~54.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RHEB variants in ClinVar

9 Conditions Cataloged

not providedTotal: 19

not specifiedTotal: 7

Isolated focal cortical dysplasia type IITotal: 1

Isolated focal cortical dysplasia type IIbTotal: 1

HemimegalencephalyTotal: 1

SeizureTotal: 1

RHEB-related disorderTotal: 1

Neurodevelopmental delayTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005614.4. 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			1 clinvar	1 clinvar		2
missense	5 clinvar	3 clinvar	18 clinvar			26
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	5	3	23	1	0	32

Highest pathogenic variant AF is 7.0720955e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 40 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005614.4	RefSeq	NP_005605.1	8	MANE Select
ENST00000262187.10	Ensembl	ENSP00000262187.5	8	MANE Select
ENST00000470370.1	Ensembl	ENSP00000417212.1	2	Standard
ENST00000472642.5	Ensembl	ENSP00000420726.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
mTOR signaling pathway - Homo sapiens (human)
Choline metabolism in cancer - Homo sapiens (human)
Autophagy - animal - Homo sapiens (human)
AMPK signaling pathway - Homo sapiens (human)

Biological Process

cell cycle arrest
signal transduction
regulation of macroautophagy
positive regulation of TOR signaling
positive regulation of oligodendrocyte differentiation

Molecular Function

magnesium ion binding
GTPase activity
protein binding
GTP binding
GDP binding

Cellular Component

Golgi membrane
spliceosomal complex
lysosomal membrane
endoplasmic reticulum membrane
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000262187
Coding exons: 8
Length: 54109
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.30	33	96.6	0.342	0.00000458	1205
Missense (PolyPhen)		2	38.917	0.051392		508
Synonymous	0.127	35	36.0	0.973	0.00000199	337
Loss of Function	3.23	0	12.1	0.00	5.79e-7	150

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Activates the protein kinase activity of mTORC1, and thereby plays a role in the regulation of apoptosis. Stimulates the phosphorylation of S6K1 and EIF4EBP1 through activation of mTORC1 signaling. Has low intrinsic GTPase activity. {ECO:0000269|PubMed:12271141, ECO:0000269|PubMed:12869586, ECO:0000269|PubMed:15340059, ECO:0000269|PubMed:15854902, ECO:0000269|PubMed:16098514, ECO:0000269|PubMed:20381137}.;

Recessive Scores

pRec: 0.171

Intolerance Scores

RVIS EVS: 0.01
RVIS percentile EVS: 54.63

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.942

Gene Damage Prediction

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