SFXN4

protein-coding

sideroflexin 4, the group of Solute carrier family 56, sideroflexins

Gene summary

This gene encodes a member of the sideroflexin family. The encoded protein is a transmembrane protein of the inner mitochondrial membrane, and is required for mitochondrial respiratory homeostasis and erythropoiesis. Mutations in this gene are associated with mitochondriopathy and macrocytic anemia. Alternatively spliced transcript variants have been found in this gene. [provided by RefSeq, Jan 2014]

MANE transcript

NM_213649.2

Inheritance

ClinVar variants

P:16U:55B:36

Top phenotype

Combined oxidative phosphorylation deficiency 18

gnomAD constraint

pLI —, LoF o/e 0.59

Max pathogenic AF

—

Genomic locus

chr10:119,140,767-119,165,714

External References & Databases

Ensembl (ENSG00000183605)

Transcript & Mutation Effects

hg38 • Region Span ~24.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014261

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *SFXN4* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of November 20, 2023. This gene encodes sideroflexin 4 but has a distinct function that differs from that of other sideroflexins (1-3), which are mitochondrial serine transporters. Sideroflexin 4 was initially thought to be involved in Fe-S cluster formation and thus important in heme synthesis, regulation of iron metabolism, and mitochondrial respiration; however subsequently sideroflexin 4 has been shown to be a complex I assembly factor important for incorporation of the ND6 subunit into complex I through an association with the mitochondrial complex I intermediate assembly (MCIA) complex (PMID: 35333655). Defects of this protein lead to complex I deficiency. *SFXN4* was first reported in relation to autosomal recessive primary mitochondrial disease in 2013 (PMID: 24119684), in two individuals with multisystem mitochondrial disease, and only one further individual has been reported to date. While various names have been given to the constellation of features seen in those with *SFXN4*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *SFXN4* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included five unique variants (three frameshift, one splice, and one protein elongation) identified in three unrelated individuals from two publications (PMIDs: 24119684, 31059822). All three reported individuals had prenatal onset and were living at the time of report. Features seen include intrauterine growth restriction, developmental delay/mild intellectual disability, muscle atrophy, tremor, incoordination, epilepsy, peripheral neuropathy, decreased vision (one with optic nerve hypoplasia, normal electroretinograms), microcephaly, and macrocytic anemia. Muscle biopsies showed complex I deficiency. Imaging in one patient revealed possible parenchymal volume loss. Elevated blood and cerebrospinal fluid lactates were also seen. This gene-disease association is also supported by its known biochemical function (PMID: 33340416), a zebrafish model (PMID: 24119684), and functional alteration in non-patient cells including a rescue experiment (PMIDs: 31873120, 35333655). In summary, there is definitive evidence to support the relationship between *SFXN4* and primary mitochondrial disease. This has been repeatedly demonstrated and upheld over time, and no convincing evidence has emerged that contradicts this gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on November 20, 2023 (SOP Version 9).

growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014261

Submitter: Ambry Genetics

growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014261

Submitter: Orphanet

growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014261

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Combined oxidative phosphorylation deficiency 18AR

Manifestation: Biochemical; Hematologic; 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

Refs: 24119684

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SFXN4 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 89

Inborn genetic diseasesTotal: 49

not specifiedTotal: 16

Growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndromeTotal: 16

SFXN4-related disorderTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_213649.2. 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			3 clinvar	17 clinvar	5 clinvar	25
missense			48 clinvar	14 clinvar		62
nonsense	2 clinvar	3 clinvar				5
start loss						0
frameshift	3 clinvar	3 clinvar	1 clinvar			7
splice donor/acceptor (+/-2bp)	1 clinvar	4 clinvar	3 clinvar			8
Total	6	10	55	31	5	107

Highest pathogenic variant AF is 0.00005273851

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_213649.2	RefSeq	NP_998814.1	14	MANE Select
ENST00000355697.7	Ensembl	ENSP00000347924.2	14	MANE Select
ENST00000369131.8	Ensembl	ENSP00000358127.4	8	Standard
ENST00000419372.5	Ensembl	ENSP00000414193.1	4	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
sfxn4	Danio rerio	Structure: nucleate erythrocyte Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

sfxn4

Danio rerio

Structure: nucleate erythrocyte

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

ion transmembrane transport
iron ion homeostasis

Molecular Function

ion transmembrane transporter activity

Cellular Component

mitochondrial inner membrane
integral component of membrane
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000355697
Coding exons: 14
Length: 24901
Individuals with no LoFs: 125688
Homozygous LoFs: 0
Heterozygous LoFs: 60
Defined: 125748
p: 0.000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.765	156	185	0.842	0.00000955	2172
Missense (PolyPhen)		31	44.446	0.69748		532
Synonymous	0.326	64	67.4	0.949	0.00000371	626
Loss of Function	1.90	15	25.3	0.592	0.00000149	265

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00027	0.00025	rare
Latino/Admixed American	0.00018	0.00017	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.00059	0.00055	rare
European (Non-Finnish)	0.00022	0.00021	rare
South Asian	0.00033	0.00033	rare
Other	0.00037	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Potential iron transporter. {ECO:0000250}.;
Disease: DISEASE: Combined oxidative phosphorylation deficiency 18 (COXPD18) [MIM:615578]: An autosomal recessive disorder of mitochondrial dysfunction characterized by intrauterine growth retardation, hypotonia, visual impairment, speech delay, and lactic acidosis associated with decreased mitochondrial respiratory chain activity. Affected patients may also show hematologic abnormalities, mainly macrocytic anemia. {ECO:0000269|PubMed:24119684}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0633

Intolerance Scores

RVIS EVS: -0.71
RVIS percentile EVS: 14.4

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.796

Gene Damage Prediction

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