NFS1
protein-codingNFS1 cysteine desulfurase, the group of Mitochondrial iron-sulfur assembly components
Gene summary
Iron-sulfur clusters are required for the function of many cellular enzymes. The proteins encoded by this gene supply inorganic sulfur to these clusters by removing the sulfur from cysteine, creating alanine in the process. This gene uses alternate in-frame translation initiation sites to generate mitochondrial forms and cytoplasmic/nuclear forms. Selection of the alternative initiation sites is determined by the cytosolic pH. The encoded proteins belong to the class-V family of pyridoxal phosphate-dependent aminotransferases. Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2010]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~31.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0030311
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0030311
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0018337
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0030311
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Cardiovascular; Neurologic
Intervention: Biochemical
Rationale: The condition can involve severe, early-onset sequelae, and mitochondrial cofactor therapy has been described as resulting in clinical improvement
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NFS1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_021100.5. 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 | 26 | 1 | 28 | ||
| missense | 1 | 79 | 3 | 83 | ||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 5 | 5 | ||||
| Total | 0 | 1 | 87 | 29 | 1 | 118 |
Highest pathogenic variant AF is 0.00006457445
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_066923.3 | 13 | MANE Select | |
| Ensembl | ENSP00000363205.3 | 13 | MANE Select | |
| RefSeq | NP_001185918.1 | 12 | Standard | |
| Ensembl | ENSP00000304740.3 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Sulfur relay system - Homo sapiens (human)
- Thiamine metabolism - Homo sapiens (human)
- [2Fe-2S] iron-sulfur cluster biosynthesis
- Mitochondrial iron-sulfur cluster biogenesis
- Metabolism
Biological Process
- sulfur amino acid metabolic process
- Mo-molybdopterin cofactor biosynthetic process
- iron incorporation into metallo-sulfur cluster
- molybdopterin cofactor biosynthetic process
- small molecule metabolic process
Molecular Function
- protein binding
- pyridoxal phosphate binding
- cysteine desulfurase activity
- protein homodimerization activity
- metal ion binding
Cellular Component
- nucleus
- nucleoplasm
- mitochondrion
- mitochondrial matrix
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000374092
- Coding exons
- 13
- Length
- 31305
- Individuals with no LoFs
- 125733
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 15
- Defined
- 125748
- p
- 0.0000596
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.41 | 196 | 260 | 0.754 | 0.0000145 | 2923 |
| Missense (PolyPhen) | 57 | 100.93 | 0.56473 | 1117 | ||
| Synonymous | 0.233 | 85 | 87.8 | 0.968 | 0.00000410 | 941 |
| Loss of Function | 3.32 | 7 | 24.8 | 0.282 | 0.00000129 | 287 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000097 | 0.000097 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalyzes the removal of elemental sulfur from cysteine to produce alanine. It supplies the inorganic sulfur for iron- sulfur (Fe-S) clusters. May be involved in the biosynthesis of molybdenum cofactor. {ECO:0000269|PubMed:18650437}.;
Recessive Scores
- pRec
- 0.380
Intolerance Scores
- LoFtool
- 0.110
- RVIS EVS
- -0.43
- RVIS percentile EVS
- 25.37
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.999
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |