ARHGEF4

protein-coding

Rho guanine nucleotide exchange factor 4, the group of Dbl family Rho GEFs|Pleckstrin homology domain containing

Gene summary

Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein coupled receptors. The protein encoded by this gene may form complex with G proteins and stimulate Rho-dependent signals. Multiple alternatively spliced transcript variants encoding different isoforms have been found, but the full-length nature of some variants has not been determined. [provided by RefSeq, Jun 2013]

MANE transcript

NM_001367493.1

Inheritance

—

ClinVar variants

U:110B:17

Top phenotype

ARHGEF4-related disorder

gnomAD constraint

pLI —, LoF o/e 0.34

Max pathogenic AF

—

Genomic locus

chr2:130,836,914-131,047,263

External References & Databases

Ensembl (ENSG00000136002)

Transcript & Mutation Effects

hg38 • Region Span ~210.3 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 ARHGEF4 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 108

ARHGEF4-related disorderTotal: 14

not providedTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001367493.1. 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				4 clinvar	1 clinvar	5
missense			109 clinvar	9 clinvar	3 clinvar	121
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	110	13	4	127

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001367493.1	RefSeq	NP_001354422.1	14	MANE Select
ENST00000409359.7	Ensembl	ENSP00000386794.3	14	MANE Select
NM_001375900.1	RefSeq	NP_001362829.1	13	Standard
NM_001375901.1	RefSeq	NP_001362830.1	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Regulation of actin cytoskeleton - Homo sapiens (human)
Regulation of Actin Cytoskeleton
Signaling by GPCR
Signal Transduction
Rho GTPase cycle

Biological Process

G protein-coupled receptor signaling pathway
lamellipodium assembly
regulation of Rho protein signal transduction
intracellular signal transduction
positive regulation of apoptotic process

Molecular Function

guanyl-nucleotide exchange factor activity
Rho guanyl-nucleotide exchange factor activity
protein binding
protein domain specific binding
Rac guanyl-nucleotide exchange factor activity

Cellular Component

cytosol
ruffle membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000326016
Coding exons: 12
Length: 210348
Individuals with no LoFs: 125732
Homozygous LoFs: 0
Heterozygous LoFs: 16
Defined: 125748
p: 0.0000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.33	361	439	0.822	0.0000279	4546
Missense (PolyPhen)		121	195.18	0.61993		2095
Synonymous	0.111	178	180	0.989	0.0000124	1290
Loss of Function	3.62	12	35.2	0.341	0.00000166	371

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000059	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000089	0.000088	rare
South Asian	0.000065	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as guanine nucleotide exchange factor (GEF) for RHOA, RAC1 and CDC42 GTPases. Binding of APC may activate RAC1 GEF activity. The APC-ARHGEF4 complex seems to be involved in cell migration as well as in E-cadherin-mediated cell-cell adhesion. Required for MMP9 up-regulation via the JNK signaling pathway in colorectal tumor cells. Involved in tumor angiogenesis and may play a role in intestinal adenoma formation and tumor progression. {ECO:0000269|PubMed:10947987, ECO:0000269|PubMed:12598901, ECO:0000269|PubMed:17145773, ECO:0000269|PubMed:17599059, ECO:0000269|PubMed:19893577}.;

Intolerance Scores

LoFtool: 0.306
RVIS EVS: -0.55
RVIS percentile EVS: 19.93

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.487

Gene Damage Prediction

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