ADAM9
protein-codingADAM metallopeptidase domain 9, the group of ADAM metallopeptidase domain containing
Gene summary
This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins, and have been implicated in a variety of biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. The protein encoded by this gene interacts with SH3 domain-containing proteins, binds mitotic arrest deficient 2 beta protein, and is also involved in TPA-induced ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor. Several alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Jul 2010]
- CORD9
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~108.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0800398
Submitter: ClinGen
The *ADAM9* gene was first reported in relation to an inherited retinal dystrophy, cone-rod dystrophy with an autosomal recessive mode of inheritance, in 2009 (Parry et al., PMID: 19409519). Affected individuals with causal variants in *ADAM9* have since been identified in a second publication (PMID: 25091951), with cases generally showing onset in the first decade of life. Presenting phenotypes include a combination of reduced visual acuity, retinal pigment epithelial abnormalities, and decreased amplitude of both the rod- and cone-based electroretinogram responses. Additional features can include macular atrophy, attenuation of retinal blood vessels, optic disc pallor, peripheral retinal degeneration, subcapsular cataracts, and/or myopia. These cases with causal variants in *ADAM9* are specifically diagnosed with cone-rod dystrophy 9. To account for a spectrum of retinal phenotypes that may be caused by variants in this gene, and in accordance with the ClinGen Lumping and Splitting guidelines, the disease entity used for this curation is ADAM9-related retinopathy (MONDO:0800398). Six suspected deleterious variants in *ADAM9* were scored as part of this curation (three nonsense and three affecting splicing), which have been collectively reported in six probands in three publications (PMID: 19409519, PMID: 25091951, PMID: 23661369). All probands were members of consanguineous families and were homozygous for the variant of interest. The mechanism of pathogenicity appears to be loss of function in *ADAM9*, characterized in at least some cases by variants predicted to trigger the absence of the gene product. One large family with co-segregation of the genotype and phenotype among affected members was scored as part of this curation, (PMID: 11581183), while other segregation evidence was not included in this curation as the maximum scoring for this evidence type had already been reached. This gene-disease association is also supported by expression evidence that retinal pigment epithelium is one of the tissue types with highest levels of *ADAM9* mRNA (PMID: 30239781). Biochemical data similarly support a structural function in the retina by showing that the ADAM9 protein mediates cell adhesion through interaction with integrins (PMID: 11162558) and regulates ocular vascularization by enhancing proteolytic shedding of the ectodomains of membrane proteins involved in angiogenesis (PMID: 19273593). A canine model of biallelic *ADAM9* loss-of-function recapitulates the visual defects, retinal atrophy, and progressive nature of the human disease state (PMID: 20691256). A murine model of biallelic *Adam9* loss-of-function further recapitulates the reduced amplitudes of both cone- and rod-based electroretinogram responses (PMID: 19409519) and indicates an underlying adhesion defect at the interface between the retina pigment epithelium and the photoreceptor outer segment. In summary, *ADAM9* is definitively associated with ADAM9-related retinopathy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a definitive classification. This classification has been approved by the ClinGen Retina GCEP on September 1st, 2022 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0013002
Submitter: Illumina
Inheritance Pattern: AR
Disease ID:MONDO:0013002
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013002
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013002
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0013002
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0015993
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Ophthalmologic
Intervention: General
Rationale: 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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ADAM9 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003816.3. 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 | 5 | 124 | 2 | 131 | ||
| missense | 247 | 12 | 1 | 260 | ||
| nonsense | 10 | 5 | 15 | |||
| start loss | 0 | |||||
| frameshift | 4 | 4 | 8 | |||
| splice donor/acceptor (+/-2bp) | 5 | 5 | 11 | 21 | ||
| Total | 19 | 14 | 263 | 136 | 3 | 435 |
Highest pathogenic variant AF is 0.000017790671
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003807.1 | 22 | MANE Select | |
| Ensembl | ENSP00000419446.2 | 22 | MANE Select | |
| Ensembl | ENSP00000369249.3 | 18 | Standard | |
| Ensembl | ENSP00000420257.1 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Copper homeostasis
- Collagen degradation
- Extracellular matrix organization
- TCR
- EGFR1
Biological Process
- activation of MAPKK activity
- membrane protein ectodomain proteolysis
- cell adhesion
- cell-matrix adhesion
- transforming growth factor beta receptor signaling pathway
Molecular Function
- metalloendopeptidase activity
- protein kinase C binding
- integrin binding
- protein binding
- collagen binding
Cellular Component
- extracellular space
- focal adhesion
- cell surface
- integral component of membrane
- basolateral plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000487273
- Coding exons
- 22
- Length
- 108276
- Individuals with no LoFs
- 125720
- Homozygous LoFs
- 1
- Heterozygous LoFs
- 27
- Defined
- 125748
- p
- 0.000111
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.90 | 329 | 442 | 0.745 | 0.0000218 | 5365 |
| Missense (PolyPhen) | 91 | 190.87 | 0.47677 | 2299 | ||
| Synonymous | -0.00570 | 155 | 155 | 1.00 | 0.00000802 | 1521 |
| Loss of Function | 4.81 | 13 | 49.5 | 0.262 | 0.00000262 | 602 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0.00020 | 0.00020 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000092 | 0.000092 | rare |
| European (Non-Finnish) | 0.000088 | 0.000088 | rare |
| South Asian | 0.00039 | 0.00036 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Cleaves and releases a number of molecules with important roles in tumorigenesis and angiogenesis, such as TEK, KDR, EPHB4, CD40, VCAM1 and CDH5. May mediate cell-cell, cell- matrix interactions and regulate the motility of cells via interactions with integrins. {ECO:0000250|UniProtKB:Q61072}.;
- Disease
- DISEASE: Cone-rod dystrophy 9 (CORD9) [MIM:612775]: An inherited retinal dystrophy characterized by retinal pigment deposits visible on fundus examination, predominantly in the macular region, and initial loss of cone photoreceptors followed by rod degeneration. This leads to decreased visual acuity and sensitivity in the central visual field, followed by loss of peripheral vision. Severe loss of vision occurs earlier than in retinitis pigmentosa, due to cone photoreceptors degenerating at a higher rate than rod photoreceptors. {ECO:0000269|PubMed:19409519}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.218
Intolerance Scores
- LoFtool
- 0.458
- RVIS EVS
- -0.2
- RVIS percentile EVS
- 38.98
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.933
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |