NUBPL

protein-coding

NUBP iron-sulfur cluster assembly factor, mitochondrial, the group of Mitochondrial respiratory chain complex assembly factors|Mitochondrial iron-sulfur assembly components

Gene summary

This gene encodes a member of the Mrp/NBP35 ATP-binding proteins family. The encoded protein is required for the assembly of the respiratory chain NADH dehydrogenase (complex I), an oligomeric enzymatic complex located in the inner mitochondrial membrane. Mutations in this gene cause mitochondrial complex I deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

Previous symbols:

C14orf127

MANE transcript

NM_025152.3

Inheritance

ClinVar variants

P:25U:99B:42

Top phenotype

Mitochondrial complex I deficiency, nuclear type 21

gnomAD constraint

pLI —, LoF o/e 0.56

Max pathogenic AF

—

Genomic locus

chr14:31,489,956-31,861,224

External References & Databases

Ensembl (ENSG00000151413)

Transcript & Mutation Effects

hg38 • Region Span ~371.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Leigh syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between NUBPL and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of February 26, 2020. The NUBPL gene encodes an iron-sulfur protein important for NADH:ubiquinone oxidoreductase (complex I) assembly. The NUBPL gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2012 (PMID: 22826544). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included five variants identified in three cases in three publications (PMIDs: 22826544, 30897263, 31917109). Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by biochemical function, expression, functional alteration in patient cells, and model systems (PMIDs: 19752196, 25613900, 20818383, 23553477, 29982452). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on February 26, 2020 (SOP Version 7).

mitochondrial complex I deficiency, nuclear type 21STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032625

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NUBPL* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of September 19, 2024. *NUBPL* encodes an iron-sulfur protein important for NADH:ubiquinone oxidoreductase (complex I) assembly. *NUBPL* was first reported in relation to autosomal recessive primary mitochondrial disease in 2010 (PMID: 20818383). While various names have been given to the constellation of features seen in those with *NUBPL*-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the NUBPL phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *NUBPL* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on February 26, 2020 (SOP V7), with a final classification of Moderate. This current curation for the association with primary mitochondrial disease includes the cases included in the LSS curation. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included nine variants (four missense, two frameshift, two splice, one complex rearrangement) in seven probands from five publications (PMIDs: 22826544, 30897263, 3191710, 20818383, 23553477). There are additional cases reported in the medical literature; however, these were not included in this curation as the maximum genetic evidence score was reached. Clinical features in affected individuals include leukodystrophy, LSS, cerebellar atrophy, corpus callosum abnormalities, developmental delay, ataxia, dystonia, dysarthria, myopathy, nystagmus, and lactic acidosis. This gene-disease association is also supported by the known biochemical function of *NUBPL* in complex I assembly, functional alteration in patient cells, rescue studies, a yeast model, and a mouse model (PMIDs: 32518176, 31787496, 20818383, 29982452, 36280881). In summary, there is definitive evidence to support the relationship between *NUBPL* and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on September 19, 2024 (SOP Version 10).

mitochondrial complex I deficiency, nuclear type 21DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0032625

Submitter: G2P

mitochondrial complex I deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100133

Submitter: Orphanet

mitochondrial complex I deficiency, nuclear type 21STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032625

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Mitochondrial complex I deficiency, nuclear type 21AR

Manifestation: Biochemical; Musculoskeletal; 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

Comments: Medical treatment (eg, riboflavin, ubiquinol) may be beneficial; Individuals may have cardiac involvement

Refs: 11743516; 20818383; 23553477; 31917109

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NUBPL variants in ClinVar

10 Conditions Cataloged

not providedTotal: 134

Inborn genetic diseasesTotal: 52

not specifiedTotal: 31

Mitochondrial complex I deficiency, nuclear type 21Total: 30

Mitochondrial complex I deficiency, nuclear type 1Total: 29

NUBPL-related disorderTotal: 13

Mitochondrial complex I deficiencyTotal: 5

Mitochondrial oxidative phosphorylation disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_025152.3. 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			6 clinvar	32 clinvar		38
missense	3 clinvar	3 clinvar	90 clinvar	10 clinvar		106
nonsense	3 clinvar	1 clinvar	1 clinvar			5
start loss		1 clinvar				1
frameshift	4 clinvar	5 clinvar	1 clinvar			10
splice donor/acceptor (+/-2bp)		5 clinvar	1 clinvar			6
Total	10	15	99	42	0	166

Highest pathogenic variant AF is 0.003732478

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 48 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_025152.3	RefSeq	NP_079428.2	11	MANE Select
ENST00000281081.12	Ensembl	ENSP00000281081.7	11	MANE Select
NM_001201573.2	RefSeq	NP_001188502.1	9	Standard
NM_001201574.2	RefSeq	NP_001188503.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

EMT transition in Colorectal Cancer
Respiratory electron transport
The citric acid (TCA) cycle and respiratory electron transport
Metabolism
Complex I biogenesis

Biological Process

iron-sulfur cluster assembly
mitochondrial respiratory chain complex I assembly
mitochondrion morphogenesis

Molecular Function

ATP binding
metal ion binding
4 iron, 4 sulfur cluster binding

Cellular Component

mitochondrion
mitochondrial matrix
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000281081
Coding exons: 11
Length: 371269
Individuals with no LoFs: 124757
Homozygous LoFs: 0
Heterozygous LoFs: 37
Defined: 124794
p: 0.000148

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.285	160	170	0.939	0.00000842	2037
Missense (PolyPhen)		46	68.199	0.67449		764
Synonymous	1.07	51	61.6	0.827	0.00000345	635
Loss of Function	1.80	11	19.6	0.561	9.85e-7	222

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000065	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00022	0.00022	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00024	0.00024	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for the assembly of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I). May deliver of one or more Fe-S clusters to complex I subunits. {ECO:0000269|PubMed:19752196}.;

Recessive Scores

pRec: 0.0910

Intolerance Scores

LoFtool: 0.704
RVIS EVS: 0.44
RVIS percentile EVS: 77.7

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.720

Gene Damage Prediction

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