ARHGEF3

protein-coding

Rho guanine nucleotide exchange factor 3, the group of Dbl family Rho GEFs

Gene summary

Rho-like GTPases are involved in a variety of cellular processes, and they are activated by binding GTP and inactivated by conversion of GTP to GDP by their intrinsic GTPase activity. Guanine nucleotide exchange factors (GEFs) accelerate the GTPase activity of Rho GTPases by catalyzing their release of bound GDP. This gene encodes a guanine nucleotide exchange factor, which specifically activates two members of the Rho GTPase family: RHOA and RHOB, both of which have a role in bone cell biology. It has been identified that genetic variation in this gene plays a role in the determination of bone mineral density (BMD), indicating the implication of this gene in postmenopausal osteoporosis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_019555.3

Inheritance

—

ClinVar variants

U:68B:3

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.31

Max pathogenic AF

—

Genomic locus

chr3:56,727,418-57,079,329

External References & Databases

Ensembl (ENSG00000163947)

Transcript & Mutation Effects

hg38 • Region Span ~351.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ARHGEF3 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 64

not providedTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_019555.3. 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			2 clinvar	1 clinvar		3
missense			65 clinvar	2 clinvar		67
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	68	3	0	71

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 45 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_019555.3	RefSeq	NP_062455.1	10	MANE Select
ENST00000296315.8	Ensembl	ENSP00000296315.3	10	MANE Select
NM_001128615.2	RefSeq	NP_001122087.1	12	Standard
NM_001128616.2	RefSeq	NP_001122088.1	10	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
arhgef3	Danio rerio	Structure: myeloid cell development Quality: absent abnormal

Gene / Model

Organism

Observed Phenotype

arhgef3

Danio rerio

Structure: myeloid cell development

Quality: absent

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Signaling by GPCR
Signal Transduction
Rho GTPase cycle
Signaling by Rho GTPases
NRAGE signals death through JNK

Biological Process

G protein-coupled receptor signaling pathway
Rho protein signal transduction
regulation of Rho protein signal transduction
positive regulation of apoptotic process
regulation of small GTPase mediated signal transduction

Molecular Function

guanyl-nucleotide exchange factor activity
Rho guanyl-nucleotide exchange factor activity
protein binding

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000338458
Coding exons: 12
Length: 351912
Individuals with no LoFs: 125733
Homozygous LoFs: 0
Heterozygous LoFs: 15
Defined: 125748
p: 0.0000596

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.08	223	329	0.677	0.0000202	3697
Missense (PolyPhen)		61	121.4	0.50248		1339
Synonymous	0.0946	124	125	0.989	0.00000767	1038
Loss of Function	3.79	11	35.3	0.311	0.00000230	338

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.000091	0.000087	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.000094	0.000092	rare
European (Non-Finnish)	0.000026	0.000026	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as guanine nucleotide exchange factor (GEF) for RhoA and RhoB GTPases. {ECO:0000269|PubMed:12221096}.;

Recessive Scores

pRec: 0.124

Intolerance Scores

LoFtool: 0.483
RVIS EVS: -0.29
RVIS percentile EVS: 33.34

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.678

Gene Damage Prediction

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