TMEM43
protein-codingtransmembrane protein 43
Gene summary
This gene belongs to the TMEM43 family. Defects in this gene are the cause of familial arrhythmogenic right ventricular dysplasia type 5 (ARVD5), also known as arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5). Arrhythmogenic right ventricular dysplasia is an inherited disorder, often involving both ventricles, and is characterized by ventricular tachycardia, heart failure, sudden cardiac death, and fibrofatty replacement of cardiomyocytes. This gene contains a response element for PPAR gamma (an adipogenic transcription factor), which may explain the fibrofatty replacement of the myocardium, a characteristic pathological finding in ARVC. [provided by RefSeq, Oct 2008]
- ARVD5
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~18.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0859235
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0020336
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011459
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0011459
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0011459
Submitter: ClinGen
The relationship between TMEM43 and arrhythmogenic right ventricular dysplasia (autosomal dominant) was evaluated using the ClinGen Clinical Validity Framework as of July 10th, 2019. Variants in TMEM43 were first reported in humans with this disease as early as 2008 (Merner et al., PMID 18313022). At least 9 variants (mostly missense) have been reported in humans. However, the pathogenicity of most of the variants is unknown. The majority of genetic evidence comes from case-level data and segregation data for one founder variant, p.Ser358Leu, which has been reported in more than 20 families with ARVC and occurred de novo in one individual (Merner et al., 2008, PMID 18313022; Christensen et al. 2011, PMID 21214875; Baskin et al., 2013, PMID 23812740; Hodgkinson et al., 2013, PMID 22725725; Milting et al., 2014, PMID 24598986). This gene-disease relationship is also supported by an animal model, expression stuies, and in vitro assays. In summary, TMEM43 is definitively associated with autosomal dominant arrhythmogenic right ventricular dysplasia . This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Arrythmogenic Right Ventricular Cardiomyopathy Gene Curation Expert Panel on October 26, 2018 (SOP Version 6).
Inheritance Pattern: AD
Disease ID:MONDO:0859235
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0011459
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013677
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Musculoskeletal
Intervention: Cardiovascular
Rationale: Individuals may manifest with arrhythmias (which have been reported in multiple individuals with EDMD 7), syncope, cardiac arrest, and sudden death, and surveillance may allow early diagnosis of sequelae; Preventive measures (eg, with antiarrhythmic pharmacologic agents and/or ICD placement) may be beneficial, though some individuals may require heart transplantation
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TMEM43 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_024334.3. 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 | 8 | 215 | 3 | 226 | ||
| missense | 1 | 1 | 493 | 71 | 3 | 569 |
| nonsense | 15 | 15 | ||||
| start loss | 4 | 4 | ||||
| frameshift | 1 | 44 | 1 | 46 | ||
| splice donor/acceptor (+/-2bp) | 1 | 22 | 23 | |||
| Total | 1 | 3 | 586 | 287 | 6 | 883 |
Highest pathogenic variant AF is 0.000005472473
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_077310.1 | 12 | MANE Select | |
| Ensembl | ENSP00000303992.5 | 12 | MANE Select | |
| RefSeq | NP_001394203.1 | 12 | Standard | |
| RefSeq | NP_001394204.1 | 12 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- miR-targeted genes in adipocytes - TarBase
- miR-targeted genes in epithelium - TarBase
- miR-targeted genes in leukocytes - TarBase
- miR-targeted genes in lymphocytes - TarBase
- miR-targeted genes in muscle cell - TarBase
Biological Process
- nuclear membrane organization
Molecular Function
- protein binding
- protein self-association
Cellular Component
- integral component of nuclear inner membrane
- endoplasmic reticulum lumen
- Golgi apparatus
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000306077
- Coding exons
- 12
- Length
- 18740
- Individuals with no LoFs
- 125638
- Homozygous LoFs
- 1
- Heterozygous LoFs
- 109
- Defined
- 125748
- p
- 0.000437
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.422 | 262 | 243 | 1.08 | 0.0000150 | 2586 |
| Missense (PolyPhen) | 69 | 76.751 | 0.89902 | 835 | ||
| Synonymous | -0.565 | 108 | 101 | 1.07 | 0.00000649 | 818 |
| Loss of Function | 0.539 | 20 | 22.8 | 0.878 | 0.00000125 | 249 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00043 | 0.00043 | rare |
| Latino/Admixed American | 0.0017 | 0.0017 | notable |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00038 | 0.00038 | rare |
| Finnish | 0.00018 | 0.00018 | rare |
| European (Non-Finnish) | 0.00024 | 0.00023 | rare |
| South Asian | 0.00020 | 0.00020 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: May have an important role in maintaining nuclear envelope structure by organizing protein complexes at the inner nuclear membrane. Required for retaining emerin at the inner nuclear membrane (By similarity). {ECO:0000250}.;
- Disease
- DISEASE: Emery-Dreifuss muscular dystrophy 7, autosomal dominant (EDMD7) [MIM:614302]: A form of Emery-Dreifuss muscular dystrophy, a degenerative myopathy characterized by weakness and atrophy of muscle without involvement of the nervous system, early contractures of the elbows, Achilles tendons and spine, and cardiomyopathy associated with cardiac conduction defects. {ECO:0000269|PubMed:21391237}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.112
Intolerance Scores
- LoFtool
- 0.856
- RVIS EVS
- 0.6
- RVIS percentile EVS
- 82.83
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 | High | High | High |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |