ISCA1

iron-sulfur cluster assembly 1, the group of Mitochondrial iron-sulfur assembly components

Basic information

Region (hg38): 9:86264546-86283102

Previous symbols: [ "HBLD2" ]

Links

ENSG00000135070 ∙ NCBI:81689 ∙ OMIM:611006 ∙ HGNC:28660 ∙ Uniprot:Q9BUE6 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• multiple mitochondrial dysfunctions syndrome 5 (Strong), mode of inheritance: AR
• multiple mitochondrial dysfunctions syndrome 5 (Limited), mode of inheritance: AR
• multiple mitochondrial dysfunctions syndrome 5 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Multiple mitochondrial dysfunctions syndrome 5	AR	General	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; Variants may additionally act as susceptibility factors (rather than being involved in Mendelian-inherited dominant disease)	Biochemical; Musculoskeletal; Neurologic; Ophthalmologic	28356563; 29767723

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ISCA1 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ISCA1 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				6	1	7
missense			12			12
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region				2		2
non coding				9	2	11
Total	0	0	12	15	3

Variants in ISCA1

This is a list of pathogenic ClinVar variants found in the ISCA1 region.

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

Position	Type	Phenotype	Significance	ClinVar
9-86266085-G-A			Benign (Jan 29, 2024)
9-86266100-C-T			Likely benign (Jul 17, 2023)
9-86266116-A-G			Uncertain significance (Apr 07, 2022)
9-86266174-C-T		Fatal multiple mitochondrial dysfunctions syndrome • Multiple mitochondrial dysfunctions syndrome 5	Conflicting classifications of pathogenicity (Mar 14, 2023)
9-86266184-T-A			Uncertain significance (Jun 08, 2022)
9-86266185-C-T			Uncertain significance (May 31, 2022)
9-86266203-GA-G			Benign (Aug 17, 2022)
9-86266208-CAT-C			Likely benign (Oct 03, 2023)
9-86271915-C-T			Benign (May 12, 2021)
9-86271988-ATGTTTG-A			Likely benign (Dec 03, 2020)
9-86272042-G-A			Uncertain significance (Jul 30, 2022)
9-86272045-T-G			Uncertain significance (Jan 22, 2024)
9-86272072-C-T			Uncertain significance (Jan 22, 2024)
9-86274170-ATT-A			Likely benign (Aug 22, 2022)
9-86274233-C-T			Uncertain significance (Oct 13, 2022)
9-86274252-G-A			Likely benign (Jul 15, 2022)
9-86274258-G-C			Likely benign (Dec 27, 2022)
9-86274260-T-A			Likely benign (Jun 07, 2023)
9-86282367-C-T			Likely benign (Jan 10, 2023)
9-86282368-G-A			Likely benign (Nov 15, 2023)
9-86282375-C-T		ISCA1-related disorder	Likely benign (Mar 20, 2020)
9-86282380-G-A			Likely benign (Jun 14, 2022)
9-86282382-G-T			Uncertain significance (Aug 27, 2021)
9-86282396-G-C			Likely benign (Dec 22, 2021)
9-86282397-G-A			Uncertain significance (Jul 11, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ISCA1	protein_coding	protein_coding	ENST00000375991	4	18216

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.171	0.776	125645	0	3	125648	0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.784	47	64.7	0.726	0.00000292	821
Missense in Polyphen		7	16.113	0.43444		235
Synonymous	0.462	21	23.9	0.880	0.00000109	254
Loss of Function	1.59	2	6.32	0.316	3.50e-7	80

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000266	0.0000264
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Involved in the maturation of mitochondrial 4Fe-4S proteins functioning late in the iron-sulfur cluster assembly pathway. Probably involved in the binding of an intermediate of Fe/S cluster assembly. {ECO:0000269|PubMed:15262227, ECO:0000269|PubMed:22323289}.
• Pathway: Mitochondrial iron-sulfur cluster biogenesis;Metabolism (Consensus)

Recessive Scores

• pRec: 0.113

Intolerance Scores

• loftool: 0.517
• rvis_EVS: 0.08
• rvis_percentile_EVS: 59.43

Haploinsufficiency Scores

• pHI: 0.281
• hipred: N
• hipred_score: 0.413
• ghis: 0.648

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.539

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Isca1
• Phenotype: mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); homeostasis/metabolism phenotype; growth/size/body region phenotype

Zebrafish Information Network

• Gene name: isca1
• Affected structure: nucleate erythrocyte
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: iron-sulfur cluster assembly;small molecule metabolic process;protein maturation by iron-sulfur cluster transfer
• Cellular component: mitochondrion;mitochondrial matrix
• Molecular function: structural molecule activity;metal ion binding;2 iron, 2 sulfur cluster binding