NFS1

NFS1 cysteine desulfurase, the group of Mitochondrial iron-sulfur assembly components

Basic information

Region (hg38): 20:35668051-35699355

Links

ENSG00000244005 ∙ NCBI:9054 ∙ OMIM:603485 ∙ HGNC:15910 ∙ Uniprot:Q9Y697 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency (Supportive), mode of inheritance: AR
• combined oxidative phosphorylation deficiency 52 (Strong), mode of inheritance: AR
• combined oxidative phosphorylation deficiency 52 (Limited), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Combined oxidative phosphorylation deficiency 52	AR	Biochemical	The condition can involve severe, early-onset sequelae, and mitochondrial cofactor therapy has been described as resulting in clinical improvement	Biochemical; Cardiovascular; Neurologic	24498631; 33457206

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NFS1 gene.

• not provided (82 variants)
• not specified (17 variants)
• Inborn genetic diseases (14 variants)
• Combined oxidative phosphorylation deficiency 52 (3 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NFS1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				15	1	16
missense			25	4		29
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)			1			1
splice region			1	4		5
non coding			1	30	23	54
Total	0	0	27	49	24

Variants in NFS1

This is a list of pathogenic ClinVar variants found in the NFS1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
20-35669362-G-T			Benign (Jun 26, 2018)
20-35669375-T-C			Likely benign (Jul 17, 2019)
20-35669429-T-C			Benign (Jun 16, 2018)
20-35669638-T-C		not specified	Uncertain significance (Sep 01, 2022)
20-35669638-T-G		not specified	Uncertain significance (Jan 17, 2024)
20-35669644-C-T			Benign/Likely benign (Jul 12, 2021)
20-35669657-T-C		not specified	Uncertain significance (Jan 04, 2022)
20-35669679-G-C			Likely benign (Dec 06, 2023)
20-35669701-G-A			Likely benign (Aug 22, 2022)
20-35669741-A-C			Benign (Jun 16, 2018)
20-35669873-G-A			Likely benign (Jun 16, 2018)
20-35672498-G-A			Benign (Jun 16, 2018)
20-35672502-C-T			Benign (Jul 07, 2018)
20-35672744-A-C		not specified	Likely benign (Feb 15, 2018)
20-35672746-T-C		NFS1-related disorder	Likely benign (Nov 22, 2022)
20-35672750-T-C			Likely benign (Mar 27, 2023)
20-35672770-C-T			Uncertain significance (Aug 02, 2022)
20-35672782-T-G		not specified	Uncertain significance (Feb 05, 2024)
20-35672863-G-A		not specified	Likely benign (Nov 27, 2023)
20-35672891-TG-T			Likely benign (Aug 30, 2018)
20-35672958-T-A			Likely benign (Jul 26, 2018)
20-35672999-A-G			Likely benign (Jul 31, 2018)
20-35673058-T-C			Benign (Jun 16, 2018)
20-35673309-A-G			Benign (Jun 16, 2018)
20-35673361-C-T			Likely benign (Jun 16, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NFS1	protein_coding	protein_coding	ENST00000374092	13	31305

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0554	0.945	125733	0	15	125748	0.0000596

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.41	196	260	0.754	0.0000145	2923
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000153	0.000152
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000972	0.0000967
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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}.
• Pathway: Sulfur relay system - Homo sapiens (human);Thiamine metabolism - Homo sapiens (human);[2Fe-2S] iron-sulfur cluster biosynthesis;Mitochondrial iron-sulfur cluster biogenesis;Metabolism;Molybdenum cofactor biosynthesis;Metabolism of water-soluble vitamins and cofactors;Metabolism of vitamins and cofactors;molybdenum cofactor biosynthesis (Consensus)

Recessive Scores

• pRec: 0.380

Intolerance Scores

• loftool: 0.110
• rvis_EVS: -0.43
• rvis_percentile_EVS: 25.37

Haploinsufficiency Scores

• pHI: 0.118
• hipred: Y
• hipred_score: 0.598
• ghis: 0.642

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.999

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Nfs1

Gene ontology

• 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;[2Fe-2S] cluster assembly;protein-containing complex assembly
• Cellular component: nucleus;nucleoplasm;mitochondrion;mitochondrial matrix;cytosol
• Molecular function: protein binding;pyridoxal phosphate binding;cysteine desulfurase activity;protein homodimerization activity;metal ion binding;iron-sulfur cluster binding