GeneBe

ISCA1

protein-coding

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

Gene summary

ISCA1 is a mitochondrial protein involved in the biogenesis and assembly of iron-sulfur clusters, which play a role in electron-transfer reactions (Cozar-Castellano et al., 2004 [PubMed 15262227]).[supplied by OMIM, Mar 2008]

Previous symbols:
  • HBLD2

MANE transcript

NM_030940.4

Inheritance

AR

ClinVar variants

P:2U:17B:9

Top phenotype

Multiple mitochondrial dysfunctions syndrome 5

gnomAD constraint

pLI —, LoF o/e 0.32

Max pathogenic AF

—

Genomic locus

chr9:86,264,546-86,283,102

External References & Databases

Ensembl (ENSG00000135070)NCBI Gene (81689)OMIM (611006)HGNC:28660GenCCUniProt (Q9BUE6)AlphaFoldClinVar (ISCA1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~18.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

multiple mitochondrial dysfunctions syndrome 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033282

Submitter: Labcorp Genetics (formerly Invitae)

multiple mitochondrial dysfunctions syndrome 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033282

Submitter: Genomics England PanelApp

multiple mitochondrial dysfunctions syndrome 5LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0033282

Submitter: Ambry Genetics

multiple mitochondrial dysfunctions syndrome 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033282

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Multiple mitochondrial dysfunctions syndrome 5AR

Manifestation: Biochemical; Musculoskeletal; Neurologic; Ophthalmologic

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; Variants may additionally act as susceptibility factors (rather than being involved in Mendelian-inherited dominant disease)

Refs: 28356563; 29767723Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ISCA1 variants in ClinVar

5 Conditions Cataloged
not providedTotal: 29
not specifiedTotal: 5
Multiple mitochondrial dysfunctions syndrome 5Total: 3
Fatal multiple mitochondrial dysfunctions syndromeTotal: 1
ISCA1-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_030940.4. 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.

EffectPLPVUSLBBSum
synonymous
9
clinvar
 9
missense
1
clinvar
1
clinvar
16
clinvar
 18
nonsense
0
start loss
0
frameshift
0
splice donor/acceptor (+/-2bp)
1
clinvar
 1
Total11179028

Highest pathogenic variant AF is 0.000009952192

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 30 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_030940.4RefSeqNP_112202.24MANE Select
ENST00000375991.9EnsemblENSP00000365159.44MANE Select
ENST00000311534.6EnsemblENSP00000339003.41Standard
ENST00000326094.4EnsemblENSP00000365157.14Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
isca1Danio rerio

Structure: nucleate erythrocyte

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Mitochondrial iron-sulfur cluster biogenesis
  • Metabolism

Biological Process

  • iron-sulfur cluster assembly
  • small molecule metabolic process
  • protein maturation by iron-sulfur cluster transfer

Molecular Function

  • structural molecule activity
  • metal ion binding
  • 2 iron, 2 sulfur cluster binding

Cellular Component

  • mitochondrion
  • mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000375991
Coding exons
4
Length
18216
Individuals with no LoFs
125645
Homozygous LoFs
0
Heterozygous LoFs
3
Defined
125648
p
0.0000119
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.7844764.70.7260.00000292821
Missense (PolyPhen)716.1130.43444235
Synonymous0.4622123.90.8800.00000109254
Loss of Function1.5926.320.3163.50e-780

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000270.000026rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

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}.;

Recessive Scores

pRec
0.113

Intolerance Scores

LoFtool
0.517
RVIS EVS
0.08
RVIS percentile EVS
59.43

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
N
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
0.539

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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