GFER

protein-coding

growth factor, augmenter of liver regeneration

Gene summary

The hepatotrophic factor designated augmenter of liver regeneration (ALR) is thought to be one of the factors responsible for the extraordinary regenerative capacity of mammalian liver. It has also been called hepatic regenerative stimulation substance (HSS). The gene resides on chromosome 16 in the interval containing the locus for polycystic kidney disease (PKD1). The putative gene product is 42% similar to the scERV1 protein of yeast. The yeast scERV1 gene had been found to be essential for oxidative phosphorylation, the maintenance of mitochondrial genomes, and the cell division cycle. The human gene is both the structural and functional homolog of the yeast scERV1 gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_005262.3

Inheritance

ClinVar variants

P:11U:74B:60

Top phenotype

Myopathy, mitochondrial progressive, with congenital cataract, hearing loss, and developmental delay

gnomAD constraint

pLI —, LoF o/e 0.87

Max pathogenic AF

—

Genomic locus

chr16:1,984,193-1,987,749

External References & Databases

Ensembl (ENSG00000127554)

Transcript & Mutation Effects

hg38 • Region Span ~3.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013116

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *GFER* and *GFER*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of September 28, 2023. *GFER* encodes growth factor ERV1-like and functions in the Disulfide Relay System (DRS, PMID: 19409522). Alterations in this protein lead to impaired mitochondrial transport of several DRS substrates, with subsequent decreased activities of the respiratory chain including complex IV. *GFER* was first reported in relation to autosomal recessive *GFER*-related primary mitochondrial disease in 2009 (PMID: 19409522). *GFER* has been associated with a single disease entity to date, autosomal recessive myopathy, mitochondrial progressive, with congenital cataract and developmental delay [OMIM#613076]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *GFER*-related primary mitochondrial disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included five variants (one missense, two frameshift, two termination) in four probands from three publications (PMIDs: 19409522, 26018198, 28155230). Age of onset was in the neonatal period. Clinical features in affected individuals include cataracts, ptosis, hearing loss, hypotonia, developmental delay, myopathy, epilepsy, and dysautonomia. Muscle biopsies show COX-negative fibers, ragged red fibers, abnormal mitochondrial morphology, and mitochondrial respiratory chain enzyme deficiencies. The mechanism of disease is loss of function. This gene-disease association is also supported by its known biochemical function, functional alteration in non-patient cells, rescue in patient cells, and model systems (PMIDs: 19409522). In summary, there is definitive evidence to support the relationship between *GFER* and *GFER*-related 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 28, 2023 (SOP Version *10).*

congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013116

Submitter: Orphanet

congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013116

Submitter: G2P

congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013116

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Myopathy, mitochondrial progressive, with congenital cataract, hearing loss, and developmental delayAR

Manifestation: Audiologic/Otolaryngologic; 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

Refs: 19409522

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GFER variants in ClinVar

6 Conditions Cataloged

not providedTotal: 135

Inborn genetic diseasesTotal: 40

Congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndromeTotal: 19

not specifiedTotal: 9

GFER-related disorderTotal: 6

Mitochondrial diseaseTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005262.3. 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				51 clinvar	1 clinvar	52
missense	2 clinvar	3 clinvar	70 clinvar	8 clinvar		83
nonsense	1 clinvar	2 clinvar	1 clinvar			4
start loss						0
frameshift	1 clinvar	2 clinvar	2 clinvar			5
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	4	7	74	59	1	145

Highest pathogenic variant AF is 0.00024323515

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005262.3	RefSeq	NP_005253.3	3	MANE Select
ENST00000248114.7	Ensembl	ENSP00000248114.6	3	MANE Select
ENST00000561710.1	Ensembl	ENSP00000456189.1	2	Standard
ENST00000567719.2	Ensembl	ENSP00000455885.1	2	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
gfer	Danio rerio	Structure: exocrine pancreas Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

gfer

Danio rerio

Structure: exocrine pancreas

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Metabolism of proteins
Mitochondrial protein import

Biological Process

regulation of signaling receptor activity
oxidation-reduction process

Molecular Function

protein binding
growth factor activity
protein disulfide oxidoreductase activity
flavin-linked sulfhydryl oxidase activity
flavin adenine dinucleotide binding

Cellular Component

extracellular region
mitochondrion
mitochondrial intermembrane space
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000248114
Coding exons: 3
Length: 3543
Individuals with no LoFs: 125599
Homozygous LoFs: 0
Heterozygous LoFs: 19
Defined: 125618
p: 0.0000756

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.195	114	108	1.05	0.00000598	1319
Missense (PolyPhen)		45	36.95	1.2179		455
Synonymous	-0.329	50	47.1	1.06	0.00000237	410
Loss of Function	0.304	6	6.86	0.875	2.97e-7	75

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.00089	0.00089	rare
East Asian	0	0.0	absent
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.000071	0.000070	rare
South Asian	0.000065	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Isoform 1: FAD-dependent sulfhydryl oxidase that regenerates the redox-active disulfide bonds in CHCHD4/MIA40, a chaperone essential for disulfide bond formation and protein folding in the mitochondrial intermembrane space. The reduced form of CHCHD4/MIA40 forms a transient intermolecular disulfide bridge with GFER/ERV1, resulting in regeneration of the essential disulfide bonds in CHCHD4/MIA40, while GFER/ERV1 becomes re- oxidized by donating electrons to cytochrome c or molecular oxygen. {ECO:0000269|PubMed:19397338, ECO:0000269|PubMed:20593814, ECO:0000269|PubMed:21383138, ECO:0000269|PubMed:22224850, ECO:0000269|PubMed:23186364, ECO:0000269|PubMed:23676665}.;

Recessive Scores

pRec: 0.304

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.897

Gene Damage Prediction

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