SLC6A4
protein-codingsolute carrier family 6 member 4, the group of Solute carrier family 6
Gene summary
This gene encodes an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. The encoded protein terminates the action of serotonin and recycles it in a sodium-dependent manner. This protein is a target of psychomotor stimulants, such as amphetamines and cocaine, and is a member of the sodium:neurotransmitter symporter family. A repeat length polymorphism in the promoter of this gene has been shown to affect the rate of serotonin uptake. There have been conflicting results in the literature about the possible effect, if any, that this polymorphism may play in behavior and depression. [provided by RefSeq, May 2019]
- HTT
- OCD1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~41.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0008114
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0005258
Submitter: ClinGen
The serotonin transporter gene (SLC6A4) was considered a candidate gene in autism spectrum disorder (ASD) based on the purported association of common coding and noncoding variants in this gene with ASD. However, these association studies, many of which were performed almost two decades ago, were underpowered, and their findings were not validated when larger samples were analyzed (2006, PMID: 16616719; meta-analysis 2008, PMID: 18286633). Several inherited missense variants identified in unrelated multiplex autism families and initially reported as rare (PMID: 15995945) are observed in gnomAD at high frequency and were not scored as evidence. Experimental evidence is available, including mouse models, but in the absence of human genetic evidence were not utilized in the scoring. In summary, there is no valid genetic evidence to support an association between SLC6A4 and autism spectrum disorder. Approved by the ClinGen ID/Autism Expert Panel 1/6/2021. Note that this gene-disease relationship was originally curated in May 2018 and given a Limited classification. Changes in scoring practices resulted in the classification being updated.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SLC6A4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001045.6. 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 | 11 | 9 | 1 | 21 | ||
| missense | 48 | 3 | 51 | |||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 0 | 1 | 60 | 12 | 1 | 74 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001036.1 | 13 | MANE Select | |
| Ensembl | ENSP00000498537.1 | 13 | MANE Select | |
| Ensembl | ENSP00000261707.3 | 13 | Standard | |
| Ensembl | ENSP00000261707.3 | 13 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Citalopram Pathway, Pharmacokinetics
- Serotonergic synapse - Homo sapiens (human)
- Selective Serotonin Reuptake Inhibitor Pathway, Pharmacodynamics
- Fluoxetine Pathway, Pharmacokinetics
- Venlafaxine Pathway, Pharmacokinetics
Biological Process
- response to hypoxia
- serotonin transport
- response to nutrient
- memory
- circadian rhythm
Molecular Function
- serotonin:sodium symporter activity
- protein binding
- monoamine transmembrane transporter activity
- myosin binding
- syntaxin-1 binding
Cellular Component
- cytosol
- plasma membrane
- integral component of plasma membrane
- endosome membrane
- endomembrane system
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000401766
- Coding exons
- 13
- Length
- 41684
- Individuals with no LoFs
- 125731
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 17
- Defined
- 125748
- p
- 0.0000676
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.93 | 272 | 378 | 0.720 | 0.0000224 | 4107 |
| Missense (PolyPhen) | 94 | 159.7 | 0.58859 | 1854 | ||
| Synonymous | 0.517 | 147 | 155 | 0.947 | 0.0000102 | 1263 |
| Loss of Function | 4.12 | 8 | 33.8 | 0.236 | 0.00000173 | 359 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000071 | 0.000070 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into the pre-synaptic terminal for re-utilization. Plays a key role in mediating regulation of the availability of serotonin to other receptors of serotonergic systems. Terminates the action of serotonin and recycles it in a sodium-dependent manner. {ECO:0000269|PubMed:17506858, ECO:0000269|PubMed:18227069, ECO:0000269|PubMed:19270731, ECO:0000269|PubMed:27049939}.;
Recessive Scores
- pRec
- 0.559
Intolerance Scores
- LoFtool
- 0.528
- RVIS EVS
- -0.6
- RVIS percentile EVS
- 18.06
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.803
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |