SMDT1
protein-codingsingle-pass membrane protein with aspartate rich tail 1
Gene summary
This gene encodes a core regulatory component of a calcium channel in the mitochondrial inner membrane. [provided by RefSeq, Apr 2017]
- C22orf32
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~4.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0016106
Submitter: LiferaOmics
Genetic evidence – Published PMID: 28600779 – Family 1 – one proband. Case-level (non-LOF start = 0.1; homozygous; no consanguinity deduction applied) = 0.1; Segregation = 0; Case-control = 0 Family 1 total = 0.1 PMID: 37454773 – Family 2 – one proband. Case-level (biallelic predicted null in AR model; homozygous; consanguinity −0.5 applied) = (1.5 − 0.5) = 1.0; Segregation = 0; Case-control = 0 Family 2 total = 1.0 PMID: 37454773 – Family 3 – one proband. Case-level (non-LOF; homozygous; consanguinity) = 0.1; Segregation = 0; Case-control = 0 Family 3 total = 0.1 Published genetic evidence total = 0.1 + 1.0 + 0.1 = 1.2 / 12 Genetic evidence – Our cases Family 1– One proband. Case-level (non-LOF; homozygous; consanguinity −0.5 applied) = 0.1; Segregation = 0; Case-control = 0 Family 1 total = 0.1 Family 2 – One proband. Case-level (non-LOF; homozygous; no consanguinity deduction applied) = 0.1; Segregation = 0; Case-control = 0 Family 2 total = 0.1 Total genetic evidence (published AR + our cases) 1.2 (published AR) + 0.2 (our cases) = 1.4 / 12 Experimental evidence – Published PMID: 37454773 – Patient fibroblasts show absence or dysfunction of EMRE (SMDT1) protein and impaired mitochondrial calcium uptake. Complementation studies restore function, supporting pathogenic loss of EMRE activity. Functional alteration (patient-derived cells with rescue; conservative single line item) = 1.0 SMDT1 encodes EMRE, an essential component of the mitochondrial calcium uniporter complex, critical for mitochondrial calcium homeostasis and muscle function. Gene function / biological plausibility = 0.5 Experimental evidence total = 1.5 / 6 Overall score Genetic evidence = 1.4 Experimental evidence = 1.5 Overall score = 2.9 / 18
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SMDT1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_033318.5. 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 | 1 | 1 | ||||
| missense | 20 | 20 | ||||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 0 | 0 | 22 | 0 | 0 | 22 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_201575.3 | 2 | MANE Select | |
| Ensembl | ENSP00000327467.3 | 2 | MANE Select | |
| Ensembl | ENSP00000402623.1 | 2 | Standard | |
| Ensembl | ENSP00000544785.1 | 2 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Transport of small molecules
- Mitochondrial calcium ion transport
- Processing of SMDT1
Biological Process
- mitochondrial calcium ion transmembrane transport
- calcium import into the mitochondrion
- mitochondrial calcium ion homeostasis
Molecular Function
- protein binding
Cellular Component
- nucleus
- mitochondrion
- mitochondrial inner membrane
- mitochondrial matrix
- integral component of mitochondrial inner membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000331479
- Coding exons
- 2
- Length
- 4594
- Individuals with no LoFs
- 125741
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 7
- Defined
- 125748
- p
- 0.0000278
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.101 | 69 | 66.7 | 1.03 | 0.00000328 | 683 |
| Missense (PolyPhen) | 28 | 28.293 | 0.98965 | 295 | ||
| Synonymous | -1.78 | 42 | 29.7 | 1.42 | 0.00000146 | 240 |
| Loss of Function | 0.894 | 1 | 2.54 | 0.394 | 1.06e-7 | 34 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.000087 | 0.000087 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Essential regulatory subunit of the mitochondrial calcium uniporter complex (uniplex), a complex that mediates calcium uptake into mitochondria (PubMed:24231807, PubMed:26774479, PubMed:27099988). Required to bridge the calcium- sensing proteins MICU1 and MICU2 with the calcium-conducting subunit MCU (PubMed:24231807). Plays a central role in regulating the uniplex complex response to intracellular calcium signaling (PubMed:27099988). Acts by mediating activation of MCU and retention of MICU1 to the MCU pore, in order to ensure tight regulation of the uniplex complex and appropriate responses to intracellular calcium signaling (PubMed:27099988). {ECO:0000269|PubMed:24231807, ECO:0000269|PubMed:26774479, ECO:0000269|PubMed:27099988}.;
Recessive Scores
- pRec
- 0.103
Intolerance Scores
- RVIS EVS
- -0.27
- RVIS percentile EVS
- 33.97
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |