GeneBe

AHI1

protein-coding

Abelson helper integration site 1, the group of WD repeat domain containing

Gene summary

This gene is apparently required for both cerebellar and cortical development in humans. This gene mutations cause specific forms of Joubert syndrome-related disorders. Joubert syndrome (JS) is a recessively inherited developmental brain disorder with several identified causative chromosomal loci. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Oct 2008]

MANE transcript

NM_001134831.2

Inheritance

AR, AD

ClinVar variants

P:347U:604B:398

Top phenotype

Joubert syndrome 3

gnomAD constraint

pLI —, LoF o/e 0.75

Max pathogenic AF

—

Genomic locus

chr6:135,283,407-135,498,434

External References & Databases

Ensembl (ENSG00000135541)NCBI Gene (54806)OMIM (608894)HGNC:21575GenCCUniProt (Q8N157)AlphaFoldClinVar (AHI1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~215.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Joubert syndrome 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012078

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

retinitis pigmentosaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019200

Submitter: Ambry Genetics

Joubert syndrome 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012078

Submitter: Natera

retinitis pigmentosaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

Joubert syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012078

Submitter: Labcorp Genetics (formerly Invitae)

Joubert syndrome 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012078

Submitter: ClinGen

AHI1 was first reported in relation to autosomal recessive Joubert Syndrome in 2004 (Ferland et al., PMID: 15322546; Dixon-Salazar et al., PMID: 15467982). The clinical features reported are consistent with Joubert syndrome with intellectual disability and brain imaging findings of molar tooth sign and cerebellar vermian hypoplasia. Additional features associated with AHI1 include polymicrogyria and a higher incidence of ocular disease (e.g. retinitis pigmentosa) compared to other genes associated with Joubert Syndrome. Liver disease and polydactyly are uncommon in AHI1 associated conditions. Six variants (missense, in-frame indel, frameshift) reported in six unique probands in three publications (PMID: 25616960, 15322546, 16453322) are included in this curation. More evidence is available in the literature, but there is sufficient evidence to classify this gene-disease pair as definitive. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by experimental evidence from a zebrafish model (PMID: 25616960), a knockout mouse model (PMID: 21623382), and biochemical functional data (PMID: 23532844). In summary, AHI1 is definitively associated with autosomal recessive Joubert Syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification has been approved by the Brain Malformations GCEP on 10/26/2021.

Joubert syndrome with ocular defectSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016364

Submitter: Orphanet

Joubert syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018772

Submitter: Orphanet

Joubert syndrome 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012078

Submitter: G2P

Joubert syndrome 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012078

Submitter: Ambry Genetics

Joubert syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012078

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Joubert syndrome 3AR

Manifestation: Neurologic; Ophthalmologic; Renal

Intervention: General

Rationale: The condition may involve multi-systemic manifestations, including sequelae affecting the renal system, and surveillance and avoidance of certain medications (eg, nephrotoxic agents) may be beneficial

Comments: The condition may involve multi-systemic manifestations, including sequelae affecting the renal and hepatic systems, and surveillance and avoidance of certain medications (eg, nephrotoxic agents) may be beneficial

Refs: 15467982; 15322546; 16155189; 16453322; 20081859; 21937992; 25616960Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AHI1 variants in ClinVar

22 Conditions Cataloged
Joubert syndromeTotal: 1318
Joubert syndrome 3Total: 534
not providedTotal: 371
Inborn genetic diseasesTotal: 188
not specifiedTotal: 177
AHI1-related disorderTotal: 161
Joubert syndrome and related disordersTotal: 21
Retinal dystrophyTotal: 11

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001134831.2. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
11
clinvar
335
clinvar
 347
missense
7
clinvar
26
clinvar
576
clinvar
59
clinvar
1
clinvar
 669
nonsense
71
clinvar
26
clinvar
4
clinvar
 101
start loss
0
frameshift
101
clinvar
58
clinvar
4
clinvar
 163
splice donor/acceptor (+/-2bp)
8
clinvar
49
clinvar
9
clinvar
3
clinvar
 69
Total18716060439711349

Highest pathogenic variant AF is 0.00011742705

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 100 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001134831.2RefSeqNP_001128303.126MANE Select
ENST00000265602.11EnsemblENSP00000265602.626MANE Select
NM_001134830.2RefSeqNP_001128302.126Standard
NM_001134832.2RefSeqNP_001128304.121Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
ahi1Danio rerio

Structure: retinal cone cell

Quality: has fewer parts of type

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Ectoderm Differentiation
  • Anchoring of the basal body to the plasma membrane
  • Cilium Assembly
  • Organelle biogenesis and maintenance

Biological Process

  • morphogenesis of a polarized epithelium
  • heart looping
  • positive regulation of receptor internalization
  • transmembrane receptor protein tyrosine kinase signaling pathway
  • central nervous system development

Molecular Function

  • protein binding
  • identical protein binding

Cellular Component

  • centrosome
  • centriole
  • cytosol
  • cell-cell junction
  • adherens junction

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000367800
Coding exons
25
Length
214245
Individuals with no LoFs
124467
Homozygous LoFs
0
Heterozygous LoFs
186
Defined
124653
p
0.000746
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.03465985961.000.00002997867
Missense (PolyPhen)135163.120.827622072
Synonymous-0.4842061971.040.000009532114
Loss of Function1.884864.30.7470.00000359827

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000800.00078rare
Latino/Admixed American0.000940.00093rare
Ashkenazi Jewish00.0absent
East Asian0.000850.00083rare
Finnish0.000660.00065rare
European (Non-Finnish)0.000830.00080rare
South Asian0.000400.00039rare
Other0.00190.0018notable

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Involved in vesicle trafficking and required for ciliogenesis, formation of primary non-motile cilium, and recruitment of RAB8A to the basal body of primary cilium. Component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes. Involved in neuronal differentiation. As a positive modulator of classical Wnt signaling, may play a crucial role in ciliary signaling during cerebellum embryonic development (PubMed:21623382). {ECO:0000250|UniProtKB:Q8K3E5, ECO:0000269|PubMed:21623382}.;
Disease
DISEASE: Joubert syndrome 3 (JBTS3) [MIM:608629]: A disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy and renal disease. Joubert syndrome type 3 shows minimal extra central nervous system involvement and appears not to be associated with renal dysfunction. {ECO:0000269|PubMed:15322546, ECO:0000269|PubMed:15467982, ECO:0000269|PubMed:16155189, ECO:0000269|PubMed:16453322, ECO:0000269|PubMed:21623382, ECO:0000269|PubMed:23532844}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.128

Intolerance Scores

LoFtool
0.998
RVIS EVS
0.46
RVIS percentile EVS
78.07

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
K
Indispensability pred.
N
Indispensability score
0.207

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
Feedback | API | MCP | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.