ANOS1
protein-codinganosmin 1, the group of Fibronectin type III domain containing|WAP four-disulfide core domain containing
Gene summary
Mutations in this gene cause the X-linked Kallmann syndrome. The encoded protein is similar in sequence to proteins known to function in neural cell adhesion and axonal migration. In addition, this cell surface protein is N-glycosylated and may have anti-protease activity. [provided by RefSeq, Jul 2008]
- KAL
- ADMLX
- KAL1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~203.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0018800
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010635
Submitter: ClinGen
ANOS1 was first reported in relation to X-linked recessive hypogonadotropic hypogonadism 1 with or without anosmia in 1991 (Legouis et al., PMID: 1913827). Hypogonadotropic hypogonadism with or without anosmia (formerly referred to as Kallman syndrome if anosmia is present) is characterized by absent or incomplete sexual maturation due to defects in gonadotropin release or action. Anosmia, or impaired sense of smell, can also be present along with variable features such as cleft palate, sensorineural hearing loss, and unilateral renal agenesis. Nine variants (missense, splicing, nonsense, frameshift) that have been reported in 9 probands in 3 publications (Hardelin et al., 1992, PMID:1518845; Jiang et al., 2020, PMID: 31669640; Nie et al., 2017, PMID: 28780519) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease association is also supported by a C. elegans model, expression studies, in vitro functional assays, and biochemical function studies (Cariboni et al., 2014, PMID:15471890; Hardelin et al., 1999, PMID: 10340754; Rugarli et al., 1993, PMID: 8513320; Rugarli et al., 2002, PMID: 11874923). In summary, ANOS1 is definitively associated with X-linked recessive hypogonadotropic hypogonadism 1 with or without anosmia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.This classification was approved by the ClinGen Syndromic Disorders GCEP on 03.28.2022 (SOP Version 8).
Inheritance Pattern: XL
Disease ID:MONDO:0010635
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0010635
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Craniofacial; Dental; Endocrine; Genitourinary; Musculoskeletal; Neurologic; Renal
Intervention: Audiologic/Otolaryngologic; Endocrine
Rationale: Surveillance in adolescence related to sexual maturation is indicated, as is monitoring of bone mineral density in order to allow early detection and treatment of disease; In order to induce and maintain secondary sex characteristics, gradually increasing doses of gonadal steroids (females: estrogen/progestin; males: testosterone/hCG) can be beneficial; Related to fertility, endocrinologic therapy (females: recombinant hCG or pulsatile GnRH therapy; males: hCG/HMG/recombinant FSH or pulsatile GnRH therapy) may be effective, though IVF may be required; As the condition may include hearing loss, recognition and interventions related to speech and language development may be beneficial
Comments: Digenic inheritance (with PROKR2) has been reported
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ANOS1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000216.4. 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 | 20 | 31 | 8 | 59 | ||
| missense | 1 | 9 | 184 | 35 | 8 | 237 |
| nonsense | 22 | 7 | 10 | 39 | ||
| start loss | 3 | 1 | 4 | |||
| frameshift | 30 | 12 | 1 | 43 | ||
| splice donor/acceptor (+/-2bp) | 6 | 10 | 13 | 29 | ||
| Total | 62 | 39 | 228 | 66 | 16 | 411 |
Highest pathogenic variant AF is 0.000010091785
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000207.2 | 14 | MANE Select | |
| Ensembl | ENSP00000262648.3 | 14 | MANE Select | |
| RefSeq | NP_001427704.1 | 9 | Standard | |
| Ensembl | ENSP00000591799.1 | 14 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| anos1a | Danio rerio | Structure: neuromast hair cell Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Signal Transduction
- Signaling by FGFR
- Signaling by Receptor Tyrosine Kinases
- FGFR1c ligand binding and activation
- FGFR1 ligand binding and activation
Biological Process
- chemotaxis
- cell adhesion
- axon guidance
- fibroblast growth factor receptor signaling pathway
- negative regulation of endopeptidase activity
Molecular Function
- serine-type endopeptidase inhibitor activity
- extracellular matrix structural constituent
- protein binding
- heparin binding
Cellular Component
- extracellular region
- extracellular space
- plasma membrane
- extracellular matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000262648
- Coding exons
- 14
- Length
- 203313
- Individuals with no LoFs
- 125730
- Homozygous LoFs
- 5
- Heterozygous LoFs
- 3
- Defined
- 125738
- p
- 0.0000318
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.885 | 221 | 261 | 0.846 | 0.0000205 | 4384 |
| Missense (PolyPhen) | 53 | 81.317 | 0.65177 | 1462 | ||
| Synonymous | 0.0928 | 107 | 108 | 0.989 | 0.00000916 | 1371 |
| Loss of Function | 4.69 | 3 | 31.3 | 0.0958 | 0.00000283 | 408 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000073 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000063 | 0.000046 | rare |
| European (Non-Finnish) | 0.000062 | 0.000044 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Has a dual branch-promoting and guidance activity, which may play an important role in the patterning of mitral and tufted cell collaterals to the olfactory cortex (By similarity). Chemoattractant for fetal olfactory epithelial cells. {ECO:0000250, ECO:0000269|PubMed:19696444}.;
- Disease
- DISEASE: Hypogonadotropic hypogonadism 1 with or without anosmia (HH1) [MIM:308700]: A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic- pituitary axis. In some cases, it is associated with non- reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). {ECO:0000269|PubMed:11297579, ECO:0000269|PubMed:15001591, ECO:0000269|PubMed:15471890, ECO:0000269|PubMed:15605412, ECO:0000269|PubMed:17054399, ECO:0000269|PubMed:17213338, ECO:0000269|PubMed:17223984, ECO:0000269|PubMed:19696444, ECO:0000269|PubMed:20530987, ECO:0000269|PubMed:21168128, ECO:0000269|PubMed:23643382, ECO:0000269|PubMed:25077900, ECO:0000269|PubMed:8504298, ECO:0000269|PubMed:8989261, ECO:0000269|PubMed:9589672}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in ANOS1 as well as in other HH-associated genes including FGFR1 and TACR3 (PubMed:23643382). {ECO:0000269|PubMed:23643382}.;
Recessive Scores
- pRec
- 0.206
Intolerance Scores
- RVIS EVS
- 0.15
- RVIS percentile EVS
- 64.74
Essentials
- Essential (gene trap)
- N