SNTA1
protein-codingsyntrophin alpha 1, the group of PDZ domain containing
Gene summary
Syntrophins are cytoplasmic peripheral membrane scaffold proteins that are components of the dystrophin-associated protein complex. This gene is a member of the syntrophin gene family and encodes the most common syntrophin isoform found in cardiac tissues. The N-terminal PDZ domain of this syntrophin protein interacts with the C-terminus of the pore-forming alpha subunit (SCN5A) of the cardiac sodium channel Nav1.5. This protein also associates cardiac sodium channels with the nitric oxide synthase-PMCA4b (plasma membrane Ca-ATPase subtype 4b) complex in cardiomyocytes. This gene is a susceptibility locus for Long-QT syndrome (LQT) - an inherited disorder associated with sudden cardiac death from arrhythmia - and sudden infant death syndrome (SIDS). This protein also associates with dystrophin and dystrophin-related proteins at the neuromuscular junction and alters intracellular calcium ion levels in muscle tissue. [provided by RefSeq, Jan 2013]
- SNT1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~35.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0013062
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0002442
Submitter: ClinGen
SNTA1 encoded Alpha-1-syntrophin, a cytoskeletal protein thought to interact with the cardiac sodium channel. Candidate genes studies identified missense variants in this gene in patients with genotype-negative LQTS (PMIDs 18591664, 19684871). One of these variants, however, is now known to be present in ~1:150 individuals of European descent, making it an unlikely cause of a rare disease. Because of the candidate gene approach, lack of segregation or case-control data and paucity of additional genetic and experimental data, this gene-disease association was classified as disputed. Note: All LQTS genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams was reviewed by the LQTS Clinical Domain Working Group. The classification and summary presented here is the conclusion of this Working Group's analysis according to evidence teams' efforts. For a detailed discussion of this group's work and the scores of all 3 teams please see "Adler et al. An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome. Circulation 2020;141(6):418-428. doi: 10.1161/CIRCULATIONAHA.119.043132”
Inheritance Pattern: AD
Disease ID:MONDO:0002442
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0013062
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular
Intervention: Cardiovascular
Rationale: Surveillance (eg, with electrocardiography), preventive measures and medical management may be beneficial to decrease morbidity and mortality
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SNTA1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003098.3. 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 | 202 | 1 | 208 | ||
| missense | 2 | 296 | 54 | 4 | 356 | |
| nonsense | 7 | 7 | ||||
| start loss | 2 | 2 | ||||
| frameshift | 14 | 14 | ||||
| splice donor/acceptor (+/-2bp) | 6 | 6 | ||||
| Total | 0 | 2 | 330 | 256 | 5 | 593 |
Highest pathogenic variant AF is 0.000025403702
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003089.1 | 8 | MANE Select | |
| Ensembl | ENSP00000217381.2 | 8 | MANE Select | |
| RefSeq | NP_001411342.1 | 8 | Standard | |
| RefSeq | NP_001411343.1 | 8 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Disopyramide Action Pathway
- Procainamide (Antiarrhythmic) Action Pathway
- Phenytoin (Antiarrhythmic) Action Pathway
- Fosphenytoin (Antiarrhythmic) Action Pathway
- Bopindolol Action Pathway
Biological Process
- regulation of heart rate
- muscle contraction
- regulation of ventricular cardiac muscle cell membrane repolarization
- ventricular cardiac muscle cell action potential
- negative regulation of peptidyl-cysteine S-nitrosylation
Molecular Function
- actin binding
- structural molecule activity
- protein binding
- calmodulin binding
- sodium channel regulator activity
Cellular Component
- cytoplasm
- cytoskeleton
- dystrophin-associated glycoprotein complex
- syntrophin complex
- lateral plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000217381
- Coding exons
- 8
- Length
- 35938
- Individuals with no LoFs
- 125724
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 24
- Defined
- 125748
- p
- 0.0000954
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.17 | 203 | 256 | 0.794 | 0.0000165 | 3151 |
| Missense (PolyPhen) | 64 | 90.114 | 0.71021 | 1105 | ||
| Synonymous | -0.0190 | 116 | 116 | 1.00 | 0.00000798 | 1124 |
| Loss of Function | 2.49 | 7 | 18.6 | 0.376 | 9.90e-7 | 218 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00018 | 0.00018 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00012 | 0.00012 | rare |
| South Asian | 0.00013 | 0.00013 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Adapter protein that binds to and probably organizes the subcellular localization of a variety of membrane proteins. May link various receptors to the actin cytoskeleton and the extracellular matrix via the dystrophin glycoprotein complex. Plays an important role in synapse formation and in the organization of UTRN and acetylcholine receptors at the neuromuscular synapse. Binds to phosphatidylinositol 4,5- bisphosphate (By similarity). {ECO:0000250}.;
- Disease
- DISEASE: Long QT syndrome 12 (LQT12) [MIM:612955]: A heart disorder characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress, and can present with a sentinel event of sudden cardiac death in infancy. {ECO:0000269|PubMed:18591664, ECO:0000269|PubMed:19684871}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.133
Intolerance Scores
- LoFtool
- 0.386
- RVIS EVS
- -0.36
- RVIS percentile EVS
- 29.16
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.717
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |