MFF

protein-coding

mitochondrial fission factor

Gene summary

This is a nuclear gene encoding a protein that functions in mitochondrial and peroxisomal fission. The encoded protein recruits dynamin-1-like protein (DNM1L) to mitochondria. There are multiple pseudogenes for this gene on chromosomes 1, 5, and X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2013]

Previous symbols:

C2orf33

MANE transcript

NM_001277062.2

Inheritance

ClinVar variants

P:9U:87B:24

Top phenotype

Encephalopathy due to defective mitochondrial and peroxisomal fission 2

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr2:227,325,151-227,357,833

External References & Databases

Ensembl (ENSG00000168958)

Transcript & Mutation Effects

hg38 • Region Span ~32.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

encephalopathy due to mitochondrial and peroxisomal fission defectMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0054865

Submitter: ClinGen

*MFF* was first reported in relation to autosomal recessive encephalopathy due to peroxisomal and mitochondrial fission defect in 2012 (Shamseldin et al., PMID: 22499341). At least 5 variants (nonsense and frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of case-level and experimental data: 9.5 points. Variants in this gene have been reported in at least 5 probands in 4 publications (PMIDs: 22499341, 30581454, 26783368, 32181496). This gene disease relationship is supported by in vitro functional assays (PMID: 18353969, 22499341, 28108524, 32224193). In summary, there is moderate evidence to support this gene-disease relationship. Although more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the Peroxisomal Disorders GCEP on April 15, 2022. It was reevaluated on May 2, 2024. As a result of this reevaluation, the classification did not change.

encephalopathy due to defective mitochondrial and peroxisomal fission 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014905

Submitter: Labcorp Genetics (formerly Invitae)

encephalopathy due to defective mitochondrial and peroxisomal fission 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014905

Submitter: G2P

encephalopathy due to defective mitochondrial and peroxisomal fission 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014905

Submitter: PanelApp Australia

Leigh syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between MFF and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of September 21, 2020. The MFF gene encodes mitochondrial fission factor, which plays an important role in mitochondrial fission. Mitochondria are dynamic organelles constantly moving along the cell cytoskeleton and form functional networks in many cells. Mitochondria undergo frequent fusion and fission events, which allow formation of these networks. Defects in MFF lead to abnormal mitochondrial morphology and dynamics. The MFF gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2016 (PMID: 26783368). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included five variants identified in four cases in three publications (PMIDs: 26783368, 30581454, 32181496). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function, expression, and functional alteration in patient cells (PMIDs: 27977873, 25613900, 26783368). 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 September 21, 2020 (SOP Version 7).

Clinical Genomic Database (CGD)

Encephalopathy due to defective mitochondrial and peroxisomal fission 2AR

Manifestation: Biochemical; 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

Refs: 22499341; 26783368; 32181496

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MFF variants in ClinVar

9 Conditions Cataloged

not providedTotal: 94

Inborn genetic diseasesTotal: 63

Encephalopathy due to defective mitochondrial and peroxisomal fission 2Total: 20

not specifiedTotal: 17

MFF-related disorderTotal: 4

Mitochondrial encephalomyopathyTotal: 1

Global developmental delayTotal: 1

Possible mitochondrial disorder - nuclear genesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001277062.2. 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				19 clinvar		19
missense			80 clinvar	5 clinvar		85
nonsense	2 clinvar	1 clinvar				3
start loss						0
frameshift	3 clinvar	1 clinvar	1 clinvar			5
splice donor/acceptor (+/-2bp)		2 clinvar	6 clinvar			8
Total	5	4	87	24	0	120

Highest pathogenic variant AF is 0.0030397393

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 202 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001277062.2	RefSeq	NP_001263991.1	7	MANE Select
ENST00000304593.14	Ensembl	ENSP00000304898.10	7	MANE Select
NM_001277061.2	RefSeq	NP_001263990.1	9	Standard
NM_001277063.2	RefSeq	NP_001263992.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

mitochondrial fission
release of cytochrome c from mitochondria
protein targeting to mitochondrion
mitochondrial fusion
regulation of mitochondrion organization

Molecular Function

protein binding
protein homodimerization activity

Cellular Component

mitochondrion
mitochondrial outer membrane
peroxisome
synaptic vesicle
cell junction

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000353339
Coding exons: 9
Length: 32684
Individuals with no LoFs: 125666
Homozygous LoFs: 0
Heterozygous LoFs: 82
Defined: 125748
p: 0.000326

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.445	187	205	0.913	0.0000121	2189
Missense (PolyPhen)		58	68.317	0.84898		807
Synonymous	0.885	61	70.5	0.866	0.00000399	694
Loss of Function	3.02	6	20.9	0.287	0.00000132	214

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.00021	0.00020	rare
Ashkenazi Jewish	0.00061	0.00060	rare
East Asian	0.00016	0.00016	rare
Finnish	0.00028	0.00028	rare
European (Non-Finnish)	0.00022	0.00022	rare
South Asian	0.0010	0.00098	notable
Other	0.00050	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role in mitochondrial and peroxisomal fission. Promotes the recruitment and association of the fission mediator dynamin-related protein 1 (DNM1L) to the mitochondrial surface. May be involved in regulation of synaptic vesicle membrane dynamics by recruitment of DNM1L to clathrin-containing vesicles. {ECO:0000269|PubMed:18353969, ECO:0000269|PubMed:23530241}.;

Recessive Scores

pRec: 0.156

Intolerance Scores

LoFtool: 0.864
RVIS EVS: -0.07
RVIS percentile EVS: 48.54

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): K
Indispensability pred.: N
Indispensability score: 0.0480

Gene Damage Prediction

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