SLC44A4
protein-codingsolute carrier family 44 member 4, the group of Solute carrier family 44
Gene summary
The protein encoded by this gene may be a sodium-dependent transmembrane transport protein involved in the uptake of choline by cholinergic neurons. Defects in this gene can cause sialidosis, a lysosomal storage disease. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2010]
- C6orf29
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~15.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0033259
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0019497
Submitter: ClinGen
SLC44A4 was first reported in relation to autosomal dominant nonsyndromic hearing loss in 2017 (Ma et al., PMID: 28013291). One variant (c.466A>G p.M156V) has been reported in one proband in one publication (PMID: 28013291) and is included in this curation. The variant was shown to segregate in the presented kindred with a LOD score of 2.1. The mechanism of pathogenicity is reported to be LOF. This gene-disease relationship is also supported by an animal model and rescue of the phenotype as well as expression level data (PMID: 28013291). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was originally evaluated by the Hearing Loss GCEP on 04/24/2018. It was reevaluated on 11/16/2022. As a result of this reevaluation, the classification did not change from limited (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0019587
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic
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 SLC44A4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_025257.3. 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 | 3 | 42 | 6 | 51 | ||
| missense | 149 | 11 | 7 | 167 | ||
| nonsense | 4 | 4 | ||||
| start loss | 1 | 1 | ||||
| frameshift | 5 | 5 | ||||
| splice donor/acceptor (+/-2bp) | 6 | 3 | 9 | |||
| Total | 0 | 0 | 168 | 56 | 13 | 237 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_079533.2 | 21 | MANE Select | |
| Ensembl | ENSP00000229729.6 | 21 | MANE Select | |
| RefSeq | NP_001171515.1 | 20 | Standard | |
| RefSeq | NP_001171516.1 | 18 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| slc44a4 | 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
- Choline metabolism in cancer - Homo sapiens (human)
- Metabolism of lipids
- Amine compound SLC transporters
- Metabolism
- Transport of bile salts and organic acids, metal ions and amine compounds
Biological Process
- phosphatidylcholine biosynthetic process
- acetylcholine biosynthetic process
- choline transport
- positive regulation of cell growth
- thiamine pyrophosphate transmembrane transport
Molecular Function
- choline transmembrane transporter activity
- thiamine pyrophosphate transmembrane transporter activity
Cellular Component
- plasma membrane
- integral component of membrane
- apical plasma membrane
- extracellular exosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000229729
- Coding exons
- 21
- Length
- 15855
- Individuals with no LoFs
- 125483
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 265
- Defined
- 125748
- p
- 0.00105
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.11 | 344 | 407 | 0.845 | 0.0000235 | 4559 |
| Missense (PolyPhen) | 123 | 164.72 | 0.74673 | 1861 | ||
| Synonymous | 1.57 | 145 | 171 | 0.847 | 0.0000106 | 1419 |
| Loss of Function | 2.05 | 29 | 43.6 | 0.665 | 0.00000234 | 453 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0040 | 0.0037 | notable |
| Latino/Admixed American | 0.00099 | 0.00098 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00033 | 0.00033 | rare |
| Finnish | 0.00056 | 0.00055 | rare |
| European (Non-Finnish) | 0.00086 | 0.00084 | rare |
| South Asian | 0.0015 | 0.0014 | notable |
| Other | 0.0021 | 0.0021 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Choline transporter that plays a role in the choline- acetylcholine system and is required to the efferent innervation of hair cells in the olivocochlear bundle for the maintenance of physiological function of outer hair cells and the protection of hair cells from acoustic injury (By similarity) (PubMed:23651124, PubMed:28013291). Also described as a thiamine pyrophosphate transporter in colon, may mediate the absorption of microbiota- generated thiamine pyrophosphate and contribute to host thiamine (vitamin B1) homeostasis (PubMed:24379411). {ECO:0000250|UniProtKB:Q7T2B0, ECO:0000269|PubMed:23651124, ECO:0000269|PubMed:24379411, ECO:0000269|PubMed:28013291}.;
- Disease
- DISEASE: Note=An interstitial deletion causing the fusion of exon 10 of CTL4 with the 3'-UTR of NEU has been detected in two patients affected by sialidosis.; DISEASE: Deafness, autosomal dominant, 72 (DFNA72) [MIM:617606]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNA72 primarily affects the middle frequencies. It gradually progresses to whole-frequency hearing loss. {ECO:0000269|PubMed:28013291}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.992
- RVIS EVS
- 1.09
- RVIS percentile EVS
- 91.9
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.101
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |