GeneBe

GBF1

protein-coding

golgi brefeldin A resistant guanine nucleotide exchange factor 1, the group of Sec7 family

Gene summary

This gene encodes a member of the Sec7 domain family. The encoded protein is a guanine nucleotide exchange factor that regulates the recruitment of proteins to membranes by mediating GDP to GTP exchange. The encoded protein is localized to the Golgi apparatus and plays a role in vesicular trafficking by activating ADP ribosylation factor 1. The encoded protein has also been identified as an important host factor for viral replication. Multiple transcript variants have been observed for this gene. [provided by RefSeq, Dec 2010]

MANE transcript

NM_001377137.1

Inheritance

AD

ClinVar variants

P:5U:258B:61

Top phenotype

Charcot-Marie-Tooth disease, axonal, type 2GG

gnomAD constraint

pLI —, LoF o/e 0.43

Max pathogenic AF

—

Genomic locus

chr10:102,245,371-102,382,899

External References & Databases

Ensembl (ENSG00000107862)NCBI Gene (8729)OMIM (603698)HGNC:4181GenCCUniProt (Q92538)AlphaFoldClinVar (GBF1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~137.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

axonal neuropathySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0004183

Submitter: Franklin by Genoox

Identification of pathogenic variants inGBF1 in four unrelated families with individuals affected by sporadic or dominant HMN/CMT2. Genomic sequencing analyses in seven affected individuals uncovered four distinct heterozygous GBF1variants, two of which occurred de novo. https://doi.org/10.1016/j.ajhg.2020.08.018

Charcot-Marie-Tooth Disease, axonal, type 2GGSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011675

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Charcot-Marie-Tooth disease, axonal, type 2GGAD

Manifestation: 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: 32937143Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GBF1 variants in ClinVar

6 Conditions Cataloged
not specifiedTotal: 235
not providedTotal: 70
Charcot-Marie-Tooth Disease, axonal, type 2GGTotal: 26
GBF1-related disorderTotal: 15
Motor axonal neuropathyTotal: 4
Charcot-Marie-Tooth disease, dominant intermediate ATotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001377137.1. 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.

EffectPLPVUSLBBSum
synonymous
6
clinvar
31
clinvar
6
clinvar
 43
missense
4
clinvar
238
clinvar
23
clinvar
1
clinvar
 266
nonsense
1
clinvar
5
clinvar
 6
start loss
0
frameshift
1
clinvar
 1
splice donor/acceptor (+/-2bp)
8
clinvar
 8
Total05258547324

Highest pathogenic variant AF is 0.000008209057

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 149 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001377137.1RefSeqNP_001364066.139MANE Select
ENST00000369983.5EnsemblENSP00000359000.439MANE Select
NM_001199378.2RefSeqNP_001186307.139Standard
NM_001199379.2RefSeqNP_001186308.139Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
gbf1Danio rerio

Structure: vasculature

Quality: hemorrhagic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Endocytosis - Homo sapiens (human)
  • Clathrin derived vesicle budding
  • trans-Golgi Network Vesicle Budding
  • Vesicle-mediated transport
  • thrombin signaling and protease-activated receptors

Biological Process

  • cell activation involved in immune response
  • endoplasmic reticulum to Golgi vesicle-mediated transport
  • retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum
  • post-Golgi vesicle-mediated transport
  • Golgi to endosome transport

Molecular Function

  • guanyl-nucleotide exchange factor activity
  • ARF guanyl-nucleotide exchange factor activity
  • protein binding
  • phosphatidylinositol-3,4,5-trisphosphate binding
  • phosphatidylinositol-3,5-bisphosphate binding

Cellular Component

  • Golgi membrane
  • mitochondrion
  • peroxisome
  • endoplasmic reticulum lumen
  • endoplasmic reticulum-Golgi intermediate compartment

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000369983
Coding exons
39
Length
137368
Individuals with no LoFs
125675
Homozygous LoFs
0
Heterozygous LoFs
73
Defined
125748
p
0.000290
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.418441.07e+30.7920.000062212137
Missense (PolyPhen)226359.080.629394116
Synonymous-0.1424134091.010.00002283786
Loss of Function5.284298.60.4260.000005991041

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000120.00012rare
Latino/Admixed American0.000290.00029rare
Ashkenazi Jewish0.000200.00020rare
East Asian0.000270.00027rare
Finnish0.000190.00018rare
European (Non-Finnish)0.000350.00035rare
South Asian0.000230.00023rare
Other0.000490.00049rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Guanine-nucleotide exchange factor (GEF) for members of the Arf family of small GTPases involved in trafficking in the early secretory pathway; its GEF activity initiates the coating of nascent vesicles via the localized generation of activated ARFs through replacement of GDP with GTP. Recruitment to cis-Golgi membranes requires membrane association of Arf-GDP and can be regulated by ARF1, ARF3, ARF4 and ARF5. Involved in the recruitment of the COPI coat complex to the endoplasmic reticulum exit sites (ERES), and the endoplasmic reticulum-Golgi intermediate (ERGIC) and cis-Golgi compartments which implicates ARF1 activation. Involved in COPI vesicle-dependent retrograde transport from the ERGIC and cis-Golgi compartments to the endoplasmic reticulum (ER) (PubMed:16926190, PubMed:17956946, PubMed:18003980, PubMed:12047556, PubMed:12808027, PubMed:19039328, PubMed:24213530). Involved in the trans-Golgi network recruitment of GGA1, GGA2, GGA3, BIG1, BIG2, and the AP-1 adaptor protein complex related to chlathrin-dependent transport; the function requires its GEF activity (probably at least in part on ARF4 and ARF5) (PubMed:23386609). Has GEF activity towards ARF1 (PubMed:15616190). Has in vitro GEF activity towards ARF5 (By similarity). Involved in the processing of PSAP (PubMed:17666033). Required for the assembly of the Golgi apparatus (PubMed:12808027, PubMed:18003980). The AMPK-phosphorylated form is involved in Golgi disassembly during mitotis and under stress conditions (PubMed:18063581, PubMed:23418352). May be involved in the COPI vesicle-dependent recruitment of PNPLA2 to lipid droplets; however, this function is under debate (PubMed:19461073, PubMed:22185782). In neutrophils, involved in G protein-coupled receptor (GPCR)-mediated chemotaxis und superoxide production. Proposed to be recruited by phosphatidylinositol-phosphates generated upon GPCR stimulation to the leading edge where it recruits and activates ARF1, and is involved in recruitment of GIT2 and the NADPH oxidase complex (PubMed:22573891). {ECO:0000250|UniProtKB:Q9R1D7, ECO:0000269|PubMed:12047556, ECO:0000269|PubMed:12808027, ECO:0000269|PubMed:15616190, ECO:0000269|PubMed:16926190, ECO:0000269|PubMed:17666033, ECO:0000269|PubMed:17956946, ECO:0000269|PubMed:18003980, ECO:0000269|PubMed:18063581, ECO:0000269|PubMed:19461073, ECO:0000269|PubMed:22185782, ECO:0000269|PubMed:22573891, ECO:0000269|PubMed:23386609, ECO:0000269|PubMed:23418352, ECO:0000269|PubMed:24213530, ECO:0000305|PubMed:19039328, ECO:0000305|PubMed:22573891}.;

Recessive Scores

pRec
0.105

Intolerance Scores

LoFtool
0.723
RVIS EVS
-3
RVIS percentile EVS
0.54

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
E
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
0.877

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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