ARFGEF1

ADP ribosylation factor guanine nucleotide exchange factor 1, the group of Armadillo like helical domain containing|ARFGEF family

Basic information

Region (hg38): 8:67173510-67343781

Links

ENSG00000066777 ∙ NCBI:10565 ∙ OMIM:604141 ∙ HGNC:15772 ∙ Uniprot:Q9Y6D6 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• schizophrenia (Limited), mode of inheritance: Unknown
• developmental delay, impaired speech, and behavioral abnormalities, with or without seizures (Moderate), mode of inheritance: AD
• developmental delay, impaired speech, and behavioral abnormalities, with or without seizures (Definitive), mode of inheritance: AD
• developmental delay, impaired speech, and behavioral abnormalities, with or without seizures (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Developmental delay, impaired speech, and behavioral abnormalities, with or without seizures	AD	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	Craniofacial; Neurologic; Ophthalmologic	31678406; 34113008

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ARFGEF1 gene.

• Inborn genetic diseases (38 variants)
• not provided (35 variants)
• Developmental delay, impaired speech, and behavioral abnormalities, with or without seizures (16 variants)
• Atypical behavior;Global developmental delay;Intellectual disability;Delayed speech and language development (5 variants)
• ARFGEF1-related condition (4 variants)
• Neurodevelopmental delay (4 variants)
• Atypical behavior;Intellectual disability;Delayed speech and language development;Global developmental delay (4 variants)
• not specified (3 variants)
• DEVELOPMENTAL DELAY, IMPAIRED SPEECH, BEHAVIORAL ABNORMALITIES, AND SEIZURES (2 variants)
• Global developmental delay;Delayed speech and language development (1 variants)
• Delayed ability to walk (1 variants)
• Neurodevelopmental disorder (1 variants)
• See cases (1 variants)
• Intellectual disability;Focal-onset seizure (1 variants)
• ARFGEF1-RELATED DISORDER (1 variants)
• Intellectual disability;Seizure;Global developmental delay (1 variants)
• Seizure (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ARFGEF1 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			1	2	6	9
missense	1		56	3		60
nonsense	9	5				14
start loss						0
frameshift	5	4	2			11
inframe indel						0
splice donor/acceptor (+/-2bp)	2	6	3			11
splice region			1		1	2
non coding			1		1	2
Total	17	15	63	5	7

Highest pathogenic variant AF is 0.00000658

Variants in ARFGEF1

This is a list of pathogenic ClinVar variants found in the ARFGEF1 region.

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

Position	Type	Phenotype	Significance	ClinVar
8-67175044-A-G			Benign (Jun 26, 2018)
8-67175183-A-G			Likely benign (Sep 05, 2018)
8-67175277-A-G		Joubert syndrome 21	Likely benign (Jul 25, 2023)
8-67175288-T-A		Joubert syndrome 21	Likely benign (Jun 04, 2023)
8-67175293-C-G			Uncertain significance (Nov 10, 2022)
8-67175307-C-T		Joubert syndrome 21	Pathogenic (Sep 27, 2022)
8-67175308-G-A		Joubert syndrome 21	Uncertain significance (Mar 31, 2022)
8-67175313-G-A		Joubert syndrome 21	Uncertain significance (Jul 03, 2023)
8-67175314-A-C		Joubert syndrome 21 • Inborn genetic diseases	Uncertain significance (Jun 28, 2022)
8-67175338-C-T		Joubert syndrome 21	Uncertain significance (May 15, 2023)
8-67175342-A-C		Joubert syndrome 21	Likely benign (Feb 26, 2021)
8-67175356-C-G		Joubert syndrome 21	Uncertain significance (Jan 24, 2024)
8-67175356-C-T		Joubert syndrome 21	Uncertain significance (Feb 24, 2022)
8-67175367-C-A		Joubert syndrome 21	Uncertain significance (Dec 07, 2023)
8-67175367-C-G		Joubert syndrome 21	Uncertain significance (Oct 05, 2022)
8-67175377-C-T		Joubert syndrome 21	Uncertain significance (Nov 15, 2019)
8-67175399-G-C		Joubert syndrome 21	Uncertain significance (Feb 23, 2022)
8-67175432-C-T		Joubert syndrome 21	Likely benign (Dec 22, 2023)
8-67175433-A-G		Joubert syndrome 21	Uncertain significance (Oct 17, 2022)
8-67175436-G-A		Joubert syndrome 21 • Inborn genetic diseases	Conflicting classifications of pathogenicity (Oct 01, 2022)
8-67175438-T-TA		Joubert syndrome 21	Uncertain significance (Jul 06, 2022)
8-67175441-G-C		Joubert syndrome 21	Uncertain significance (Apr 15, 2021)
8-67175454-C-T		not specified • Joubert syndrome 21	Benign/Likely benign (Jan 25, 2024)
8-67175456-G-A		Joubert syndrome 21	Likely benign (Aug 09, 2021)
8-67175475-C-T			Likely benign (Jun 28, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ARFGEF1	protein_coding	protein_coding	ENST00000262215	39	170166

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	3.70e-11	125662	0	86	125748	0.000342

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	5.37	479	943	0.508	0.0000464	12216
Missense in Polyphen		118	383.68	0.30755		5103
Synonymous	-0.378	334	325	1.03	0.0000163	3401
Loss of Function	8.58	8	101	0.0792	0.00000530	1237

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000436	0.000430
Ashkenazi Jewish	0.00	0.00
East Asian	0.00280	0.00261
Finnish	0.000139	0.000139
European (Non-Finnish)	0.0000814	0.0000791
Middle Eastern	0.00280	0.00261
South Asian	0.000527	0.000457
Other	0.000528	0.000489

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Promotes guanine-nucleotide exchange on ARF1 and ARF3. Promotes the activation of ARF1/ARF3 through replacement of GDP with GTP. Involved in vesicular trafficking. Required for the maintenance of Golgi structure; the function may be independent of its GEF activity. Required for the maturaion of integrin beta-1 in the Golgi. Involved in the establishment and persistence of cell polarity during directed cell movement in wound healing. Proposed to act as A kinase-anchoring protein (AKAP) and may mediate crosstalk between Arf and PKA pathways. Inhibits GAP activity of MYO9B probably through competetive RhoA binding. The function in the nucleus remains to be determined. {ECO:0000269|PubMed:12571360, ECO:0000269|PubMed:15644318, ECO:0000269|PubMed:17227842, ECO:0000269|PubMed:20360857, ECO:0000269|PubMed:22084092}.
• Pathway: Endocytosis - Homo sapiens (human);thrombin signaling and protease-activated receptors;adp-ribosylation factor (Consensus)

Recessive Scores

• pRec: 0.283

Intolerance Scores

• loftool: 0.444
• rvis_EVS: -1.75
• rvis_percentile_EVS: 2.37

Haploinsufficiency Scores

• pHI: 0.899
• hipred: Y
• hipred_score: 0.736
• ghis: 0.657

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.839

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Arfgef1
• Phenotype: cellular 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); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Gene ontology

• Biological process: exocytosis;Golgi organization;endomembrane system organization;protein transport;vesicle-mediated transport;negative regulation of actin filament polymerization;neuron projection development;regulation of ARF protein signal transduction;negative regulation of GTPase activity;positive regulation of GTPase activity;positive regulation of protein kinase B signaling;positive regulation of protein glycosylation in Golgi;positive regulation of wound healing;regulation of establishment of cell polarity
• Cellular component: Golgi membrane;nucleoplasm;nucleolus;Golgi apparatus;trans-Golgi network;cytosol;nuclear matrix;small nuclear ribonucleoprotein complex;perinuclear region of cytoplasm
• Molecular function: guanyl-nucleotide exchange factor activity;ARF guanyl-nucleotide exchange factor activity;GTPase activator activity;protein binding;myosin binding;protein kinase A regulatory subunit binding