ARHGEF15

protein-coding

Rho guanine nucleotide exchange factor 15, the group of Dbl family Rho GEFs

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. This gene encodes a protein that functions as a specific guanine nucleotide exchange factor for RhoA. It also interacts with ephrin A4 in vascular smooth muscle cells. Two alternatively spliced transcripts variants that encode the same protein have been found for this gene. [provided by RefSeq, Aug 2010]

MANE transcript

NM_173728.4

Inheritance

ClinVar variants

U:417B:185

Top phenotype

Early-infantile DEE

gnomAD constraint

pLI —, LoF o/e 0.44

Max pathogenic AF

—

Genomic locus

chr17:8,310,241-8,322,514

External References & Databases

Ensembl (ENSG00000198844)

Transcript & Mutation Effects

hg38 • Region Span ~12.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

schizophreniaNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0005090

Submitter: Labcorp Genetics (formerly Invitae)

genetic developmental and epileptic encephalopathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ARHGEF15 variants in ClinVar

7 Conditions Cataloged

Early-infantile DEETotal: 627

not specifiedTotal: 134

not providedTotal: 39

ARHGEF15-related disorderTotal: 15

Developmental and epileptic encephalopathyTotal: 8

Prostate cancerTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_173728.4. 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			2 clinvar	141 clinvar	14 clinvar	157
missense			387 clinvar	24 clinvar	6 clinvar	417
nonsense			7 clinvar			7
start loss						0
frameshift			14 clinvar			14
splice donor/acceptor (+/-2bp)			7 clinvar			7
Total	0	0	417	165	20	602

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_173728.4	RefSeq	NP_776089.2	15	MANE Select
ENST00000361926.8	Ensembl	ENSP00000355026.3	15	MANE Select
NM_025014.2	RefSeq	NP_079290.1	15	Standard
ENST00000421050.2	Ensembl	ENSP00000412505.1	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

VEGFA-VEGFR2 Signaling Pathway
Signaling by GPCR
Signal Transduction
Rho GTPase cycle
Signaling by Rho GTPases

Biological Process

regulation of Rho protein signal transduction
positive regulation of GTPase activity
regulation of catalytic activity
positive regulation of stress fiber assembly
retina vasculature morphogenesis in camera-type eye

Molecular Function

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

Cellular Component

cytoplasm
dendrite

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000361926
Coding exons: 15
Length: 12271
Individuals with no LoFs: 125678
Homozygous LoFs: 0
Heterozygous LoFs: 66
Defined: 125744
p: 0.000262

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.715	475	521	0.912	0.0000318	5274
Missense (PolyPhen)		167	202.66	0.82404		2014
Synonymous	1.04	191	210	0.909	0.0000113	1918
Loss of Function	3.15	16	36.5	0.438	0.00000185	382

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00051	0.00049	rare
Latino/Admixed American	0.00049	0.00046	rare
Ashkenazi Jewish	0.00014	0.000099	rare
East Asian	0.00083	0.00082	rare
Finnish	0.000051	0.000046	rare
European (Non-Finnish)	0.00019	0.00018	rare
South Asian	0.00015	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Specific GEF for RhoA activation. Does not activate RAC1 or CDC42. Regulates vascular smooth muscle contractility. Negatively regulates excitatory synapse development by suppressing the synapse-promoting activity of EPHB2. {ECO:0000269|PubMed:12775584}.;

Recessive Scores

pRec: 0.101

Intolerance Scores

LoFtool: 0.372
RVIS EVS: 0.54
RVIS percentile EVS: 81.09

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Indispensability pred.: E
Indispensability score: 0.667

Gene Damage Prediction

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