C19orf12
protein-codingchromosome 19 open reading frame 12
Gene summary
This gene encodes a small transmembrane protein. Mutations in this gene are a cause of neurodegeneration with brain iron accumulation-4 (NBIA4), but the specific function of the encoded protein is unknown. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]
- SPG43
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~16.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013674
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0013674
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0014024
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013674
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013674
Submitter: ClinGen
The C19orf12 gene is located on chromosome 19 at 19p12 and encodes for a transmembrane glycine zipper-containing mitochondrial protein. This protein is involved in the mitochondrial and lipid metabolism. C19orf12 was first reported in relation to Autosomal Recessive Neurodegeneration with Brain Iron Accumulation (NBIA) in 2011. (Hartig et al 2011, PMID:21981780). Hartig et al first described 25 NBIA cases with homozygous, or compound heterozygous frameshift, or missense variants in C19orf12. A total of 18 NBIA cases were found to have homozygous common founder mutation c.204_214del11 (p.Gly69ArgfsX10) with all individuals having common MRI brain findings of hypointensities in the globus pallidus and substantia nigra, and presenting features including speech, gait difficulties, extrapyramidal features (oromandibular dystonia, generalized dystonia and parkinsonism), spasticity, hyperreflexia, psychiatric symptoms, and optic atrophy. C19orf12 was previously reported in two Malian sisters presenting with spastic paraplegia with gait difficulty, spasticity and peripheral neuropathy without brain abnormalities. (Landoure et al 2013 (PMID: 23857908); Meilleur et al 2009 (PMID: 20039086)). Both disease assertions have overlapping features in the central and peripheral nervous systems, with NBIA individuals having additional MRI brain abnormal findings in globus pallidus/substantia nigra, and ophthalmological features (e.g. Optic atrophy). Evidence supporting this gene-disease relationship includes case-level and experimental data. Biallelic variants in C19orf12 (including nonsense, frameshift, splice, and missense variants, small indel, duplication and deletion) were identified in at least 35 patients with clinical features suggestive of Autosomal Recessive Neurodegeneration with Brain Iron Accumulation (NBIA) (Hartig et al 2011, PMID:21981780; Hogarth et al 2012, PMID:23269600; Deschauer et al 2012, PMID: 22584950; Akçakaya et al 2019, PMID: 31804703; Dezfouli et al 2013, PMID:23166001; Landouré et al 2013, PMID: 23857908). At least 11 unique variants (nonsense, frameshift, splice, and missense variants, small indel, duplication and deletion) have been reported in humans. This gene-disease association is supported by biochemical function studies, non-human model organism studies, and functional alteration analysis. (Hartig et al 2011, PMID:21981780; Landouré et al 2013, PMID: 23857908; Mori et al 2019, PMID 31548400; Mignani et al 2020, PMID: 33425903; Iuso et al 2014, PMID:24586779; Venco et al 2015, PMID: 26136767; Shao et al 2022, PMID: 35182730). In summary, the C19orf12 gene is definitively associated with Autosomal Recessive Neurodegeneration with Brain Iron Accumulation (NBIA) and Autosomal Recessive Spastic Paraplegia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: SD
Disease ID:MONDO:0013674
Submitter: Illumina
Inheritance Pattern: AR
Disease ID:MONDO:0014024
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0013674
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0013674
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0013674
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0013674
Submitter: ClinGen
The C19orf12 gene is located on chromosome 19 at 19p12 and encodes for a transmembrane glycine zipper-containing mitochondrial protein. This protein is involved in the mitochondrial and lipid metabolism. C19orf12 was first reported in relation to Autosomal Recessive Neurodegeneration with Brain Iron Accumulation (NBIA) in 2011. (Hartig et al 2011, PMID:21981780). Hartig et al first described 25 NBIA cases with homozygous, or compound heterozygous frameshift, or missense variants in C19orf12. A total of 18 NBIA cases were found to have homozygous common founder mutation c.204_214del11 (p.Gly69ArgfsX10) with all individuals having common MRI brain findings of hypointensities in the globus pallidus and substantia nigra, and presenting features including speech, gait difficulties, extrapyramidal features (oromandibular dystonia, generalized dystonia and parkinsonism), spasticity, hyperreflexia, psychiatric symptoms, and optic atrophy. C19orf12 was previously reported in two Malian sisters presenting with spastic paraplegia with gait difficulty, spasticity and peripheral neuropathy without brain abnormalities. (Landoure et al 2013 (PMID: 23857908); Meilleur et al 2009 (PMID: 20039086)). Both disease assertions have overlapping features in the central and peripheral nervous systems, with NBIA individuals having additional MRI brain abnormal findings in globus pallidus/substantia nigra, and ophthalmological features (e.g. Optic atrophy). Monfrini et al first published a case report of a patient with NBIA with novel heterozygous pathogenic variant c.265_266delAT (p.Met89Glyfs*12) in C19orf12 (Monfrini et al 2018, PMID:29295770). This was followed by Gregory et al that published 18 heterozygous cases of C19orf12-related NBIA from 13 families (Gregory et al 2019, PMID:3108752). The individuals with autosomal dominant form of NBIA were clinically similar to individuals with autosomal recessive form of NBIA. Gregory et al proposed that the nonsense truncating variants located in the final exon of C19rf12 impairs the function of the wild-type protein, producing a dominant-negative effect and leading to loss of function (Gregory et al 2019, PMID:3108752). Another proposed dominant disease mechanism was haploinsufficiency (Gregory et al 2019, PMID: 3108752) Evidence supporting this gene-disease relationship includes case-level and experimental data. Heterozygous variants in C19orf12 (including nonsense and frameshift) were identified in at least 19 patients with clinical features suggestive of Autosomal Dominant Neurodegeneration with Brain Iron Accumulation (NBIA) (Gregory et al 2019, PMID: 3108752; Monfrini et al 2018, PMID:29295770; Rickman et al 2021, PMID:33260061; Fraser et al 2021, PMID:34041867; Yang et al 2022, PMID:35432442). At least 13 unique variants (nonsense and frameshift) have been reported in humans and the information of six unique variants in C19orf12 is available in ClinVar database. This gene-disease association is supported by biochemical function studies, non-human model organism studies, and functional alteration analysis. (Hartig et al 2011, PMID:21981780; Landouré et al 2013, PMID: 23857908; Mori et al 2019, PMID 31548400; Mignani et al 2020, PMID: 33425903; Iuso et al 2014, PMID:24586779; Venco et al 2015, PMID: 26136767; Shao et al 2022, PMID: 35182730). In summary, the C19orf12 gene has a moderate association with Autosomal Dominant Neurodegeneration with Brain Iron Accumulation (NBIA).
Inheritance Pattern: AR
Disease ID:MONDO:0014024
Submitter: Genomics England PanelApp
Clinical Genomic Database (CGD)
Manifestation: Neurologic
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 C19orf12 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_031448.6. 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 | 42 | 42 | ||||
| missense | 3 | 9 | 75 | 4 | 1 | 92 |
| nonsense | 3 | 2 | 2 | 7 | ||
| start loss | 2 | 2 | ||||
| frameshift | 7 | 11 | 8 | 26 | ||
| splice donor/acceptor (+/-2bp) | 3 | 2 | 5 | |||
| Total | 13 | 25 | 89 | 46 | 1 | 174 |
Highest pathogenic variant AF is 0.00008116461
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_113636.2 | 2 | MANE Select | |
| Ensembl | ENSP00000313332.9 | 2 | MANE Select | |
| RefSeq | NP_001026896.3 | 2 | Standard | |
| RefSeq | NP_001242975.1 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- autophagy
- apoptotic process
- response to oxidative stress
- mitochondrial calcium ion homeostasis
Cellular Component
- mitochondrion
- endoplasmic reticulum
- cytosol
- integral component of membrane
- mitochondrial membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000392278
- Coding exons
- 3
- Length
- 14644
- Individuals with no LoFs
- 125714
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 32
- Defined
- 125746
- p
- 0.000127
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.390 | 84 | 94.7 | 0.887 | 0.00000631 | 976 |
| Missense (PolyPhen) | 17 | 20.886 | 0.81395 | 265 | ||
| Synonymous | -0.785 | 52 | 45.3 | 1.15 | 0.00000379 | 322 |
| Loss of Function | 1.52 | 1 | 4.46 | 0.224 | 1.92e-7 | 55 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00019 | 0.00018 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000092 | 0.000092 | rare |
| European (Non-Finnish) | 0.00019 | 0.00018 | rare |
| South Asian | 0.00013 | 0.00013 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Disease
- DISEASE: Neurodegeneration with brain iron accumulation 4 (NBIA4) [MIM:614298]: A neurodegenerative disorder associated with iron accumulation in the brain, primarily in the basal ganglia. NBIA4 results in speech difficulty, extrapyramidal signs, oromandibular and generalized dystonia, and parkinsonism. Most patients have progressive involvement of the corticospinal tract, with spasticity, hyperreflexia, and extensor plantar responses. {ECO:0000269|PubMed:21981780, ECO:0000269|PubMed:22508347, ECO:0000269|PubMed:22584950, ECO:0000269|PubMed:22704260, ECO:0000269|PubMed:23269600, ECO:0000269|PubMed:23278385, ECO:0000269|PubMed:23521069, ECO:0000269|PubMed:23857908, ECO:0000269|PubMed:25592411, ECO:0000269|PubMed:26136767, ECO:0000269|PubMed:26187298}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spastic paraplegia 43, autosomal recessive (SPG43) [MIM:615043]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SP43 is characterized by childhood onset of progressive spasticity affecting the lower and upper limbs. {ECO:0000269|PubMed:23857908}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.0410
- RVIS EVS
- 0.26
- RVIS percentile EVS
- 70.06
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 |