ARHGEF9

Cdc42 guanine nucleotide exchange factor 9, the group of Pleckstrin homology domain containing|Dbl family Rho GEFs

Basic information

Region (hg38): X:63634967-63809274

Links

ENSG00000131089 ∙ NCBI:23229 ∙ OMIM:300429 ∙ HGNC:14561 ∙ Uniprot:O43307 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• developmental and epileptic encephalopathy, 8 (Supportive), mode of inheritance: XL
• developmental and epileptic encephalopathy, 8 (Strong), mode of inheritance: XL
• X-linked complex neurodevelopmental disorder (Moderate), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Developmental and epileptic encephalopathy 8	XL	General	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	Neurologic	15215304; 21633362; 22612257
As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ARHGEF9 gene.

• Developmental and epileptic encephalopathy, 8 (20 variants)
• not provided (4 variants)
• Inborn genetic diseases (3 variants)
• Global developmental delay (1 variants)
• ARHGEF9-related neurodevelopmental disorder (1 variants)
• Developmental disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ARHGEF9 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			3	81	3	87
missense	1	6	132	11	4	154
nonsense	14	3	2			19
start loss			1			1
frameshift	6	2	1			9
inframe indel			1			1
splice donor/acceptor (+/-2bp)	2	5	2			9
splice region	1	1	10	16		28
non coding			12	54	19	85
Total	23	16	154	146	26

Variants in ARHGEF9

This is a list of pathogenic ClinVar variants found in the ARHGEF9 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
X-63635344-T-C		Global developmental delay	Uncertain significance (Mar 17, 2020)
X-63637846-CTG-C			Benign (Aug 10, 2019)
X-63637846-CTGTG-C			Benign (Aug 10, 2019)
X-63637846-C-CTG			Benign (Aug 10, 2019)
X-63637882-C-G		Epilepsy	Likely benign (-)
X-63638021-G-C		not specified • ARHGEF9-related disorder	Likely benign (Jan 26, 2016)
X-63638039-A-G		Developmental and epileptic encephalopathy, 8	Uncertain significance (Jan 25, 2020)
X-63638042-G-A			Uncertain significance (Sep 16, 2019)
X-63638042-G-C		Inborn genetic diseases	Uncertain significance (Nov 17, 2023)
X-63638049-C-T		Developmental and epileptic encephalopathy, 8	Likely benign (Jan 17, 2024)
X-63638052-G-A		Developmental and epileptic encephalopathy, 8	Benign (Jun 13, 2022)
X-63638054-T-C			Likely benign (Feb 27, 2019)
X-63638060-T-G		Developmental and epileptic encephalopathy, 8	Uncertain significance (Jul 16, 2019)
X-63638064-C-T		Developmental and epileptic encephalopathy, 8	Uncertain significance (Aug 05, 2021)
X-63638067-G-C		Developmental and epileptic encephalopathy, 8	Uncertain significance (Nov 11, 2020)
X-63638070-T-A		Developmental and epileptic encephalopathy, 8 • Inborn genetic diseases • not specified	Likely benign (Feb 07, 2024)
X-63638082-G-A		Developmental and epileptic encephalopathy, 8 • Inborn genetic diseases	Likely benign (Aug 16, 2022)
X-63638083-C-T		Developmental and epileptic encephalopathy, 8	Uncertain significance (Jan 08, 2024)
X-63638094-G-A		not specified	Likely benign (Feb 15, 2016)
X-63638100-C-A		Developmental and epileptic encephalopathy, 8	Uncertain significance (Jul 09, 2023)
X-63638103-A-C		Developmental and epileptic encephalopathy, 8	Conflicting classifications of pathogenicity (Aug 30, 2022)
X-63638103-A-G		Developmental and epileptic encephalopathy, 8	Likely benign (Jul 23, 2022)
X-63638108-C-T		Developmental and epileptic encephalopathy, 8	Conflicting classifications of pathogenicity (Aug 10, 2022)
X-63638110-T-C		Developmental and epileptic encephalopathy, 8	Likely benign (Dec 19, 2023)
X-63638112-C-T		Developmental and epileptic encephalopathy, 8 • Inborn genetic diseases	Likely benign (Jan 07, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ARHGEF9	protein_coding	protein_coding	ENST00000253401	10	150580

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.999	0.00110	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.04	86	210	0.409	0.0000170	3481
Missense in Polyphen		11	74.501	0.14765		1188
Synonymous	0.192	77	79.2	0.973	0.00000673	877
Loss of Function	4.12	0	19.8	0.00	0.00000140	323

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Acts as guanine nucleotide exchange factor (GEF) for CDC42. Promotes formation of GPHN clusters (By similarity). {ECO:0000250|UniProtKB:Q9QX73, ECO:0000269|PubMed:10559246}.
• Pathway: Ectoderm Differentiation;Signaling by GPCR;Signal Transduction;GABA A receptor activation;Rho GTPase cycle;Neuronal System;Signaling by Rho GTPases;NRAGE signals death through JNK;Death Receptor Signalling;p75 NTR receptor-mediated signalling;GABA receptor activation;Neurotransmitter receptors and postsynaptic signal transmission;Transmission across Chemical Synapses;G alpha (12/13) signalling events;GPCR downstream signalling;Regulation of CDC42 activity;Cell death signalling via NRAGE, NRIF and NADE (Consensus)

Recessive Scores

• pRec: 0.115

Intolerance Scores

• loftool: 0.0652
• rvis_EVS: -0.12
• rvis_percentile_EVS: 44.89

Haploinsufficiency Scores

• pHI: 0.242
• hipred: Y
• hipred_score: 0.825
• ghis: 0.540

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.538

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Arhgef9
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: arhgef9b
• Affected structure: caudal vein plexus
• Phenotype tag: abnormal
• Phenotype quality: malformed

Gene ontology

• Biological process: G protein-coupled receptor signaling pathway;regulation of Rho protein signal transduction;positive regulation of apoptotic process;regulation of small GTPase mediated signal transduction;regulation of postsynaptic specialization assembly
• Cellular component: cytosol;postsynaptic density;cell junction;postsynaptic membrane;GABA-ergic synapse
• Molecular function: guanyl-nucleotide exchange factor activity;Rho guanyl-nucleotide exchange factor activity