RHOA

protein-coding

ras homolog family member A, the group of Rho family GTPases

Gene summary

This gene encodes a member of the Rho family of small GTPases, which cycle between inactive GDP-bound and active GTP-bound states and function as molecular switches in signal transduction cascades. Rho proteins promote reorganization of the actin cytoskeleton and regulate cell shape, attachment, and motility. Overexpression of this gene is associated with tumor cell proliferation and metastasis. Multiple alternatively spliced variants have been identified. [provided by RefSeq, Sep 2015]

Previous symbols:

ARH12
ARHA

MANE transcript

NM_001664.4

Inheritance

ClinVar variants

P:4U:19B:2

Top phenotype

Ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies

gnomAD constraint

pLI —, LoF o/e 0.14

Max pathogenic AF

—

Genomic locus

chr3:49,359,139-49,412,998

External References & Databases

Ensembl (ENSG00000067560)

Transcript & Mutation Effects

hg38 • Region Span ~53.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomaliesLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0032884

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomaliesAD

Manifestation: Craniofacial; Dental; Dermatologic; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Causative variants have been postzygotic mosaic (and not detected via blood-based testing)

Refs: 31570889

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RHOA variants in ClinVar

8 Conditions Cataloged

Ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomaliesTotal: 6

not providedTotal: 5

not specifiedTotal: 4

RHOA-related disorderTotal: 2

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

neuro-ectodermal phenotypeTotal: 1

HemihypertrophyTotal: 1

Inborn genetic diseasesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001664.4. 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	3 clinvar	1 clinvar	16 clinvar			20
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	3	1	19	1	1	25

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 69 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001664.4	RefSeq	NP_001655.1	4	MANE Select
ENST00000418115.6	Ensembl	ENSP00000400175.1	4	MANE Select
NM_001313941.2	RefSeq	NP_001300870.1	4	Standard
NM_001313943.2	RefSeq	NP_001300872.1	5	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
rhoab	Danio rerio	Structure: somite border Quality: hypoplastic abnormal

Gene / Model

Organism

Observed Phenotype

rhoab

Danio rerio

Structure: somite border

Quality: hypoplastic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Platelet activation - Homo sapiens (human)
Focal adhesion - Homo sapiens (human)
mTOR signaling pathway - Homo sapiens (human)
Oxytocin signaling pathway - Homo sapiens (human)
T cell receptor signaling pathway - Homo sapiens (human)

Biological Process

response to hypoxia
angiotensin-mediated vasoconstriction involved in regulation of systemic arterial blood pressure
alpha-beta T cell lineage commitment
regulation of systemic arterial blood pressure by endothelin
regulation of transcription by RNA polymerase II

Molecular Function

GTPase activity
protein binding
GTP binding
myosin binding
GDP binding

Cellular Component

nucleus
cytoplasm
endosome
endoplasmic reticulum membrane
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000418115
Coding exons: 4
Length: 53854
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	3.36	13	114	0.114	0.00000622	1274
Missense (PolyPhen)		0	32.164	0		418
Synonymous	-0.431	46	42.4	1.08	0.00000239	369
Loss of Function	2.13	1	7.14	0.140	2.98e-7	100

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: Regulates a signal transduction pathway linking plasma membrane receptors to the assembly of focal adhesions and actin stress fibers. Involved in a microtubule-dependent signal that is required for the myosin contractile ring formation during cell cycle cytokinesis. Plays an essential role in cleavage furrow formation. Required for the apical junction formation of keratinocyte cell-cell adhesion. Stimulates PKN2 kinase activity. May be an activator of PLCE1. Activated by ARHGEF2, which promotes the exchange of GDP for GTP. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. The MEMO1-RHOA-DIAPH1 signaling pathway plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. It controls the localization of APC and CLASP2 to the cell membrane, via the regulation of GSK3B activity. In turn, membrane-bound APC allows the localization of the MACF1 to the cell membrane, which is required for microtubule capture and stabilization. Regulates a signal transduction pathway linking plasma membrane receptors to the assembly of focal adhesions and actin stress fibers. Involved in a microtubule-dependent signal that is required for the myosin contractile ring formation during cell cycle cytokinesis. Plays an essential role in cleavage furrow formation. Required for the apical junction formation of keratinocyte cell-cell adhesion. May be an activator of PLCE1. Activated by ARHGEF2, which promotes the exchange of GDP for GTP. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. The MEMO1-RHOA-DIAPH1 signaling pathway plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. It controls the localization of APC and CLASP2 to the cell membrane, via the regulation of GSK3B activity. In turn, membrane-bound APC allows the localization of the MACF1 to the cell membrane, which is required for microtubule capture and stabilization (By similarity). Regulates KCNA2 potassium channel activity by reducing its location at the cell surface in response to CHRM1 activation; promotes KCNA2 endocytosis (PubMed:9635436, PubMed:19403695). {ECO:0000250, ECO:0000269|PubMed:12900402, ECO:0000269|PubMed:16103226, ECO:0000269|PubMed:16236794, ECO:0000269|PubMed:19934221, ECO:0000269|PubMed:20937854, ECO:0000269|PubMed:20974804, ECO:0000269|PubMed:8910519, ECO:0000269|PubMed:9121475, ECO:0000269|PubMed:9635436}.; FUNCTION: (Microbial infection) Serves as a target for the yopT cysteine peptidase from Yersinia pseudotuberculosis, which causes gastrointestinal disorders. {ECO:0000269|PubMed:12062101, ECO:0000269|PubMed:12538863}.;

Recessive Scores

pRec: 0.104

Intolerance Scores

RVIS EVS: -0.01
RVIS percentile EVS: 52.85

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.982