ARL6

ADP ribosylation factor like GTPase 6, the group of ARF GTPase family

Basic information

Region (hg38): 3:97764521-97801229

Previous symbols: [ "BBS3" ]

Links

ENSG00000113966 ∙ NCBI:84100 ∙ OMIM:608845 ∙ HGNC:13210 ∙ Uniprot:Q9H0F7 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Bardet-Biedl syndrome 3 (Definitive), mode of inheritance: AR
• retinitis pigmentosa 55 (Definitive), mode of inheritance: AR
• Bardet-Biedl syndrome 3 (Strong), mode of inheritance: AR
• Bardet-Biedl syndrome 3 (Strong), mode of inheritance: AR
• retinitis pigmentosa (Supportive), mode of inheritance: AD
• Bardet-Biedl syndrome (Supportive), mode of inheritance: AR
• Bardet-Biedl syndrome 3 (Strong), mode of inheritance: AR
• retinitis pigmentosa 55 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Bardet-Biedl syndrome 3	AR	Cardiovascular; Endocrine	Individuals have been described with congenital heart anomalies, and awareness may enable early diagnosis and management; Medical management of obesity with melanocortin-4 receptor (MC4R) agonist (setmelanotide) may be beneficial	Cardiovascular; Craniofacial; Endocrine; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic; Renal	7987310; 9714014; 15258860; 15314642; 19956407; 19858128; 20301537; 23219996; 36356613
Variants may modify the severity of BBS due to variants in other BBS-associated genes

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ARL6 gene.

• Bardet-Biedl syndrome 3;Retinitis pigmentosa 55 (12 variants)
• Retinitis pigmentosa 55;Bardet-Biedl syndrome 3 (7 variants)
• Bardet-Biedl syndrome 3 (5 variants)
• Bardet-Biedl syndrome (4 variants)
• Retinitis pigmentosa 55 (2 variants)
• Retinitis pigmentosa (2 variants)
• Bardet-Biedl syndrome 1, modifier of (1 variants)
• Bardet-Biedl syndrome 1 (1 variants)
• not provided (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ARL6 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				40		40
missense	7	2	58	1		68
nonsense	8	2	1			11
start loss	1					1
frameshift	4		1			5
inframe indel			2			2
splice donor/acceptor (+/-2bp)	2	8				10
splice region	1		6	18		25
non coding			11	42	11	64
Total	22	12	73	83	11

Highest pathogenic variant AF is 0.0000197

Variants in ARL6

This is a list of pathogenic ClinVar variants found in the ARL6 region.

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

Position	Type	Phenotype	Significance	ClinVar
3-97764689-C-T		Bardet-Biedl syndrome 3 • Retinitis pigmentosa	Uncertain significance (Jan 13, 2018)
3-97764693-A-G		Bardet-Biedl syndrome 3 • Retinitis pigmentosa	Uncertain significance (Jan 12, 2018)
3-97764765-C-T		Bardet-Biedl syndrome • Retinitis Pigmentosa, Recessive	Likely benign (Jun 14, 2016)
3-97764798-G-A		Bardet-Biedl syndrome 3 • Retinitis pigmentosa	Uncertain significance (Jan 12, 2018)
3-97764859-T-C		Bardet-Biedl syndrome 3 • Retinitis pigmentosa	Uncertain significance (Jan 12, 2018)
3-97764868-A-C		Retinitis pigmentosa • Bardet-Biedl syndrome 3	Uncertain significance (Jan 13, 2018)
3-97764934-C-G		Bardet-Biedl syndrome 3 • Retinitis pigmentosa	Uncertain significance (Jan 13, 2018)
3-97766620-A-T		Retinitis pigmentosa • Bardet-Biedl syndrome 3	Conflicting classifications of pathogenicity (Jan 13, 2018)
3-97768078-C-T		Bardet-Biedl syndrome 3	Uncertain significance (Aug 12, 2021)
3-97768108-A-G		Bardet-Biedl syndrome 3;Retinitis pigmentosa 55	Pathogenic (Sep 27, 2022)
3-97768111-G-C		Retinitis pigmentosa 55;Bardet-Biedl syndrome 3	Uncertain significance (Jan 21, 2022)
3-97768111-G-T		Bardet-Biedl syndrome 3;Retinitis pigmentosa 55 • Bardet-Biedl syndrome 1 • ARL6-related disorder	Pathogenic (Jun 10, 2023)
3-97768124-G-A		Retinitis pigmentosa 55;Bardet-Biedl syndrome 3	Uncertain significance (Sep 27, 2022)
3-97768124-G-C		Bardet-Biedl syndrome 3;Retinitis pigmentosa 55	Uncertain significance (Sep 24, 2021)
3-97768131-A-C		Retinitis pigmentosa 55;Bardet-Biedl syndrome 3	Likely benign (Dec 09, 2023)
3-97768135-T-C		Retinitis pigmentosa 55;Bardet-Biedl syndrome 3	Likely benign (Mar 09, 2023)
3-97768137-G-C		Retinitis pigmentosa 55;Bardet-Biedl syndrome 3	Uncertain significance (Jul 19, 2022)
3-97768140-T-A		Bardet-Biedl syndrome 3;Retinitis pigmentosa 55 • ARL6-related disorder	Likely benign (Dec 29, 2023)
3-97768145-TGAA-T		Bardet-Biedl syndrome 3;Retinitis pigmentosa 55 • Retinitis pigmentosa 55 • ARL6-related disorder	Uncertain significance (Feb 04, 2022)
3-97768150-A-G		Bardet-Biedl syndrome 3;Retinitis pigmentosa 55 • ARL6-related disorder	Uncertain significance (Aug 26, 2021)
3-97768156-G-A		Bardet-Biedl syndrome 3;Retinitis pigmentosa 55 • Bardet-Biedl syndrome 1;Bardet-Biedl syndrome 3;Retinitis pigmentosa;Retinitis pigmentosa 55 • ARL6-related disorder • Inborn genetic diseases	Uncertain significance (Dec 15, 2022)
3-97768159-G-A		Retinitis pigmentosa 55;Bardet-Biedl syndrome 3	Uncertain significance (May 16, 2023)
3-97768161-T-A		ARL6-related disorder	Likely benign (May 02, 2024)
3-97768162-C-G		ARL6-related disorder	Uncertain significance (Dec 07, 2023)
3-97768168-T-C		Bardet-Biedl syndrome 3;Retinitis pigmentosa 55	Likely benign (Jan 19, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ARL6	protein_coding	protein_coding	ENST00000463745	7	36589

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0101	0.948	125721	0	8	125729	0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.555	81	96.3	0.841	0.00000460	1228
Missense in Polyphen		22	32.632	0.67418		425
Synonymous	0.176	32	33.3	0.961	0.00000164	332
Loss of Function	1.77	5	11.5	0.436	5.47e-7	148

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000908	0.0000904
Ashkenazi Jewish	0.00	0.00
East Asian	0.000109	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.0000265	0.0000264
Middle Eastern	0.000109	0.000109
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Involved in membrane protein trafficking at the base of the ciliary organelle. Mediates recruitment onto plasma membrane of the BBSome complex which would constitute a coat complex required for sorting of specific membrane proteins to the primary cilia (PubMed:20603001). Together with BBS1, is necessary for correct trafficking of PKD1 to primary cilia (By similarity). Together with the BBSome complex and LTZL1, controls SMO ciliary trafficking and contributes to the sonic hedgehog (SHH) pathway regulation (PubMed:22072986). May regulate cilia assembly and disassembly and subsequent ciliary signaling events such as the Wnt signaling cascade (PubMed:20207729). Isoform 2 may be required for proper retinal function and organization (By similarity). {ECO:0000250|UniProtKB:O88848, ECO:0000269|PubMed:20207729, ECO:0000269|PubMed:20603001, ECO:0000269|PubMed:22072986}.
• Disease: DISEASE: Bardet-Biedl syndrome 3 (BBS3) [MIM:600151]: A syndrome characterized by usually severe pigmentary retinopathy, early- onset obesity, polydactyly, hypogenitalism, renal malformation and mental retardation. Secondary features include diabetes mellitus, hypertension and congenital heart disease. Bardet-Biedl syndrome inheritance is autosomal recessive, but three mutated alleles (two at one locus, and a third at a second locus) may be required for clinical manifestation of some forms of the disease. {ECO:0000269|PubMed:15258860, ECO:0000269|PubMed:15314642, ECO:0000269|PubMed:23219996}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Retinitis pigmentosa 55 (RP55) [MIM:613575]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:19956407}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: BBSome-mediated cargo-targeting to cilium;Cargo trafficking to the periciliary membrane;Cilium Assembly;Organelle biogenesis and maintenance (Consensus)

Recessive Scores

• pRec: 0.208

Intolerance Scores

• loftool: 0.310
• rvis_EVS: -0.1
• rvis_percentile_EVS: 46.2

Haploinsufficiency Scores

• pHI: 0.0837
• hipred: Y
• hipred_score: 0.579
• ghis: 0.636

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.539

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Arl6
• Phenotype: adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); cellular phenotype; craniofacial phenotype; vision/eye phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); reproductive system phenotype; skeleton 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)

Zebrafish Information Network

• Gene name: arl6
• Affected structure: whole organism
• Phenotype tag: abnormal
• Phenotype quality: decreased length

Gene ontology

• Biological process: protein targeting to membrane;intracellular protein transport;determination of left/right symmetry;brain development;visual perception;regulation of smoothened signaling pathway;retina layer formation;Wnt signaling pathway;vesicle-mediated transport;melanosome transport;fat cell differentiation;protein polymerization;cilium assembly;protein localization to cilium;protein localization to non-motile cilium;protein transport from ciliary membrane to plasma membrane
• Cellular component: cytoplasm;cytosol;axonemal microtubule;plasma membrane;cilium;axoneme;membrane;membrane coat;extracellular exosome
• Molecular function: protein binding;GTP binding;phospholipid binding;metal ion binding