NDUFB7

protein-coding

NADH:ubiquinone oxidoreductase subunit B7, the group of NADH:ubiquinone oxidoreductase supernumerary subunits

Gene summary

The protein encoded by this gene is a subunit of the multisubunit NADH:ubiquinone oxidoreductase (complex I). Mammalian complex I is composed of 45 different subunits. It is located at the mitochondrial inner membrane. This protein has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. [provided by RefSeq, Jul 2008]

MANE transcript

NM_004146.6

Inheritance

ClinVar variants

U:26B:5

Top phenotype

Mitochondrial complex I deficiency, nuclear type 39

gnomAD constraint

pLI —, LoF o/e 0.78

Max pathogenic AF

—

Genomic locus

chr19:14,566,078-14,572,066

External References & Databases

Ensembl (ENSG00000099795)

Transcript & Mutation Effects

hg38 • Region Span ~6.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial diseaseLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NDUFB7* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of April 29, 2024. The *NDUFB7* gene encodes the NADH:ubiquinone oxidoreductase (complex I) subunit B7, an accessory subunit of complex I. Defects of this protein lead to complex I deficiency. The first and only report of *NDUFB7* in relation to autosomal recessive primary mitochondrial disease was in 2021 (PMID: 33502047). *NDUFB7* has been associated with a single disease entity to date; mitochondrial complex I deficiency, nuclear type 39 [OMIM# 620135]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and is considered a primary mitochondrial disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included one homozygous intronic variant identified in one case from one publication (PMID: 33502047). The proband presented in the prenatal period at gestational week 25 with intrauterine growth restriction, intrauterine anemia, and cardiomegaly. Clinical features present after birth included lactic acidosis, pulmonary hypertension, cryptorchidism, hypospadias, and cystic and dysplastic corpus callosum. The child died at 55 days old from cardiopulmonary respiratory failure. There was evidence of complex I dysfunction in fibroblasts. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416) and by knockout studies in HEK293T cells showing severe reduction in complex I assembly (PMID: 27626371). In summary, there is limited 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/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on April 29, 2024 (SOP Version 10).

mitochondrial complex I deficiency, nuclear type 39LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0859320

Submitter: G2P

mitochondrial complex I deficiency, nuclear type 39MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0859320

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NDUFB7 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 24

not providedTotal: 2

Mitochondrial complex I deficiency, nuclear type 39Total: 2

Mitochondrial disorder due to a defect in assembly or maturation of the respiratory chain complexesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004146.6. 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 clinvar	2 clinvar		3
missense			24 clinvar	3 clinvar		27
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	26	5	0	31

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004146.6	RefSeq	NP_004137.2	3	MANE Select
ENST00000215565.3	Ensembl	ENSP00000215565.1	3	MANE Select
ENST00000593353.5	Ensembl	ENSP00000473120.1	2	Standard
ENST00000897442.1	Ensembl	ENSP00000567501.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Retrograde endocannabinoid signaling - Homo sapiens (human)
Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human)
Alzheimer,s disease - Homo sapiens (human)
Huntington,s disease - Homo sapiens (human)
Thermogenesis - Homo sapiens (human)

Biological Process

mitochondrial electron transport, NADH to ubiquinone
mitochondrial respiratory chain complex I assembly

Molecular Function

NADH dehydrogenase (ubiquinone) activity

Cellular Component

mitochondrion
mitochondrial inner membrane
mitochondrial respiratory chain complex I
mitochondrial intermembrane space

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000215565
Coding exons: 3
Length: 5985
Individuals with no LoFs: 121876
Homozygous LoFs: 0
Heterozygous LoFs: 15
Defined: 121891
p: 0.0000615

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.267	86	93.3	0.922	0.00000633	871
Missense (PolyPhen)		28	32.33	0.86608		249
Synonymous	0.140	34	35.1	0.970	0.00000195	253
Loss of Function	0.451	4	5.10	0.784	2.18e-7	56

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000064	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.00012	0.00012	rare
South Asian	0	0.0	absent
Other	0.00017	0.00017	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis. Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. {ECO:0000269|PubMed:27626371}.;

Recessive Scores

pRec: 0.154

Intolerance Scores

LoFtool: 0.622
RVIS EVS: -0.34
RVIS percentile EVS: 30.07

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): H
Indispensability pred.: N
Indispensability score: 0.458

Gene Damage Prediction

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