SLC9A9
protein-codingsolute carrier family 9 member A9, the group of Solute carrier family 9
Gene summary
This gene encodes a sodium/proton exchanger that is a member of the solute carrier 9 protein family. The encoded protein localizes the to the late recycling endosomes and may play an important role in maintaining cation homeostasis. Mutations in this gene are associated with autism susceptibility 16 and attention-deficit/hyperactivity disorder. [provided by RefSeq, Mar 2012]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~583.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0013258
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0005258
Submitter: ClinGen
SLC9A9 was first reported in relation to autism spectrum disorder in 2008 (Morrow et al., 2008 PMID: 18621663). A homozygous deletion upstream of SLC9A9 (also known as NHE9) as well as several heterozygous variants (one nonsense and several missense) were reported in this gene; the sequence variants were later found to have high population frequencies in gnomAD. According to gnomAD (v.2.1.1), SLC9A9 is not constrained for loss of function variants (pLI=0) or missense variants (z-score=-0.25). Previously, a pericentric inversion of chromosome 3 disrupting SLC9A9 was reported in an extended pedigree with intellectual disability and behavioral problems (PMID: 14569117). The other inversion breakpoint affected DOCK3, a brain-expressed gene involved in neurodevelopmental disorders, and the inversion did not always segregate with the phenotype, therefore this family was not scored. An inherited exonic deletion of SLC9A9 in an individual with autism spectrum disorder and epilepsy (PMID: 27123481), and two nonsense variants in individuals with autism spectrum disorder, including one reported several times in gnomAD (PMID: 26185613), were also not scored. As of March 2020, there is no valid human evidence supporting a role of SLC9A9 in autism spectrum disorder. As such, we did not score any functional evidence. Genetic evidence: 0 points. Experimental evidence: 0 points. In summary, the evidence supporting the relationship between SLC9A9 and autosomal dominant autism spectrum disorder is disputed. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 10/08/2020.
Inheritance Pattern: AD
Disease ID:MONDO:0013258
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Neurologic
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 SLC9A9 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_173653.4. 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 | 2 | 18 | 7 | 27 | ||
| missense | 89 | 5 | 2 | 96 | ||
| nonsense | 1 | 3 | 4 | |||
| start loss | 0 | |||||
| frameshift | 1 | 3 | 4 | |||
| splice donor/acceptor (+/-2bp) | 4 | 4 | ||||
| Total | 1 | 1 | 101 | 23 | 9 | 135 |
Highest pathogenic variant AF is 0.000026641917
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_775924.1 | 16 | MANE Select | |
| Ensembl | ENSP00000320246.6 | 16 | MANE Select | |
| Ensembl | ENSP00000418627.1 | 3 | Standard | |
| Ensembl | ENSP00000419090.2 | 2 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Sodium/Proton exchangers
- Transport of inorganic cations/anions and amino acids/oligopeptides
- SLC-mediated transmembrane transport
- Transport of small molecules
Biological Process
- ion transport
- regulation of intracellular pH
- potassium ion transmembrane transport
- sodium ion import across plasma membrane
- proton transmembrane transport
Molecular Function
- protein binding
- sodium:proton antiporter activity
- potassium:proton antiporter activity
Cellular Component
- plasma membrane
- integral component of membrane
- late endosome membrane
- recycling endosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000316549
- Coding exons
- 16
- Length
- 583310
- Individuals with no LoFs
- 125655
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 93
- Defined
- 125748
- p
- 0.000370
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.247 | 360 | 347 | 1.04 | 0.0000178 | 4238 |
| Missense (PolyPhen) | 143 | 153.48 | 0.93175 | 1817 | ||
| Synonymous | -1.39 | 154 | 134 | 1.15 | 0.00000790 | 1230 |
| Loss of Function | 1.77 | 23 | 34.1 | 0.674 | 0.00000176 | 402 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00031 | 0.00031 | rare |
| Latino/Admixed American | 0.00038 | 0.00038 | rare |
| Ashkenazi Jewish | 0.0016 | 0.0016 | notable |
| East Asian | 0.0011 | 0.00092 | notable |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00030 | 0.00030 | rare |
| South Asian | 0.00020 | 0.00020 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: May act in electroneutral exchange of protons for Na(+) across membranes. Involved in the effusion of Golgi luminal H(+) in exchange for cytosolic cations. Involved in organelle ion homeostasis by contributing to the maintenance of the unique acidic pH values of the Golgi and post-Golgi compartments in the cell. {ECO:0000269|PubMed:15522866}.;
- Disease
- DISEASE: Autism 16 (AUTS16) [MIM:613410]: A complex multifactorial, pervasive developmental disorder characterized by impairments in reciprocal social interaction and communication, restricted and stereotyped patterns of interests and activities, and the presence of developmental abnormalities by 3 years of age. Most individuals with autism also manifest moderate mental retardation. AUTS16 can be associated with epilepsy. {ECO:0000269|PubMed:18621663}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.884
- RVIS EVS
- -0.86
- RVIS percentile EVS
- 10.89
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.280
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |