TFG

protein-coding

trafficking from ER to golgi regulator

Gene summary

There are several documented fusion oncoproteins encoded partially by this gene. This gene also participates in several oncogenic rearrangements resulting in anaplastic lymphoma and mixoid chondrosarcoma, and may play a role in the NF-kappaB pathway. Multiple transcript variants have been found for this gene. [provided by RefSeq, Sep 2010]

MANE transcript

NM_006070.6

Inheritance

AR, AD

ClinVar variants

P:6U:237B:111

Top phenotype

Neuropathy, hereditary motor and sensory, Okinawa type; Spastic paraplegia 57

gnomAD constraint

pLI —, LoF o/e 0.26

Max pathogenic AF

—

Genomic locus

chr3:100,709,295-100,748,964

External References & Databases

Ensembl (ENSG00000114354)

Transcript & Mutation Effects

hg38 • Region Span ~39.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary spastic paraplegia 57SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014295

Submitter: Orphanet

hereditary motor and sensory neuropathy, Okinawa typeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011468

Submitter: PanelApp Australia

hereditary spastic paraplegia 57STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014295

Submitter: PanelApp Australia

hereditary motor and sensory neuropathy, Okinawa typeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011468

Submitter: Orphanet

hereditary spastic paraplegia 57STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014295

Submitter: Labcorp Genetics (formerly Invitae)

hereditary motor and sensory neuropathy, Okinawa typeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011468

Submitter: Labcorp Genetics (formerly Invitae)

hereditary spastic paraplegia 57LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014295

Submitter: LiferaOmics

Genetic evidence – Published PMID: 23479643 – Family 1 – two affected sibs (counted as one proband). Case-level (AR homozygous; non-LOF start = 0.1; no consanguinity deduction applied) = 0.1; Segregation (two affected sibs segregating with homozygous variant; parents confirmed heterozygous carriers) = 0.5; Case-control = 0 Family 1 total = 0.6 PMID: 27601211– Family 2 – one proband. Case-level (AR homozygous; non-LOF start = 0.1; consanguineous family) = 0.1; Segregation = 0; Case-control = 0 Family 2 total = 0.1 PMID: 33767317 – Family 3 – two affected sibs (counted as one proband). Case-level (AR homozygous; non-LOF start = 0.1; consanguineous family) = 0.1; Segregation (two affected sibs segregating with homozygous variant in AR model) = 0.5;Case-control = 0 Family 3 total = 0.6 PMID: 33767317– Family 4 – one proband. Case-level (AR homozygous; non-LOF start = 0.1; consanguineous family) = 0.1; Segregation = 0; Case-control = 0 Family 4 total = 0.1 PMID: 38837630– Family 5 – one proband. Case-level (AR homozygous; non-LOF start = 0.1; no consanguinity deduction applied [not reported]) = 0.1; Segregation = 0; Case-control = 0 Family 5 total = 0.1 PMID: 27492651 – Family 6– one proband Case-level (AR homozygous; non-LOF start = 0.1; no consanguinity deduction applied [not reported]) = 0.1; Segregation = 0.5; Case-control = 0 Family 6 total = 0.6 PMID: 27492651 – Family 7– one proband (independent from family 6) Case-level (AR homozygous; non-LOF start = 0.1; no consanguinity deduction applied [not reported]) = 0.1; Segregation = 0.5; Case-control = 0 Family 7 total = 0.6 Published genetic evidence total = 2.7 / 12 Genetic evidence – Our cases Family 1 – one proband. Case-level (AR homozygous; non-LOF start = 0.1; no consanguinity deduction applied [non-consanguineous]) = 0.1; Segregation = 0; Case-control = 0 Family 1 total = 0.1 Family 2 – one proband. Case-level (AR homozygous; non-LOF start = 1; no consanguinity deduction applied [non-consanguineous]) = 0.1; Segregation = 0; Case-control = 0 Family 2 total = 0.1 Total genetic evidence (published AR + our cases) 2.7 (published AR) + 0.2 (our cases) = 2.9 / 12 Experimental evidence – Published PMID: 23479643 – Functional alteration (engineered cell systems). The pathogenic p.Arg106Cys variant was expressed but failed to assemble properly into the normal octameric TFG complex, disrupting oligomerization critical for ER organization and axonal maintenance. Functional alteration (cell-based mechanistic evidence supporting AR functional impairment) = 0.5 PMID: 27601211– Functional alteration (in vitro oligomerization assay). The p.Arg22Trp variant disrupted TFG oligomer formation, consistent with loss of normal multimerization capacity. Functional alteration (independent variant showing similar mechanistic defect) = 0.5 PMID: 38837630– Functional alteration (cellular localization and secretion assays). The p.Lys59Asn variant caused abnormal protein distribution, impaired oligomer assembly, reduced secretion efficiency, and decreased cell viability. Functional alteration (additional independent mechanistic support) = 1.0 Experimental evidence total = 2.0 / 6 Overall score Genetic evidence = 2.9 Experimental evidence = 2.0 Overall score = 4.9 / 18

autosomal dominant Charcot-Marie-Tooth disease type 2 due to TFG mutationSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018567

Submitter: Orphanet

Clinical Genomic Database (CGD)

Neuropathy, hereditary motor and sensory, Okinawa type; Spastic paraplegia 57AR

Manifestation: Musculoskeletal; 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: 17906970; 22883144; 23479643; 23553329; 25098539

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TFG variants in ClinVar

10 Conditions Cataloged

Hereditary motor and sensory neuropathy, Okinawa typeTotal: 370

Hereditary spastic paraplegia 57Total: 368

not providedTotal: 105

Inborn genetic diseasesTotal: 65

TFG-related disorderTotal: 40

not specifiedTotal: 25

Charcot-Marie-Tooth diseaseTotal: 1

Amyotrophic Lateral Sclerosis with Sensory NeuropathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006070.6. 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			4 clinvar	97 clinvar	2 clinvar	103
missense	2 clinvar	3 clinvar	218 clinvar	10 clinvar	2 clinvar	235
nonsense		1 clinvar	7 clinvar			8
start loss						0
frameshift			7 clinvar			7
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	2	4	237	107	4	354

Highest pathogenic variant AF is 0.0000427838

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 123 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006070.6	RefSeq	NP_006061.2	7	MANE Select
ENST00000240851.9	Ensembl	ENSP00000240851.4	7	MANE Select
NM_001007565.2	RefSeq	NP_001007566.1	7	Standard
NM_001195478.2	RefSeq	NP_001182407.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Pathways in cancer - Homo sapiens (human)
Thyroid cancer - Homo sapiens (human)
Vesicle-mediated transport
Membrane Trafficking
Post-translational protein modification

Biological Process

endoplasmic reticulum to Golgi vesicle-mediated transport
positive regulation of I-kappaB kinase/NF-kappaB signaling
COPII vesicle coating

Molecular Function

protein binding
identical protein binding

Cellular Component

Golgi membrane
cytoplasm
cytosol
endoplasmic reticulum exit site

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000240851
Coding exons: 7
Length: 39606
Individuals with no LoFs: 125739
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125747
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.33	166	222	0.748	0.0000115	2579
Missense (PolyPhen)		21	41.309	0.50837		530
Synonymous	-1.09	87	75.0	1.16	0.00000372	796
Loss of Function	3.31	6	23.2	0.259	0.00000130	233

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000053	0.000053	rare
South Asian	0.000034	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role in the normal dynamic function of the endoplasmic reticulum (ER) and its associated microtubules (PubMed:23479643, PubMed:27813252). {ECO:0000269|PubMed:23479643, ECO:0000269|PubMed:27813252}.;
Disease: DISEASE: Neuropathy, hereditary motor and sensory, Okinawa type (HMSNO) [MIM:604484]: A neurodegenerative disorder characterized by young adult onset of proximal muscle weakness and atrophy, muscle cramps, and fasciculations, with later onset of distal sensory impairment. The disorder is slowly progressive and clinically resembles amyotrophic lateral sclerosis. {ECO:0000269|PubMed:22883144, ECO:0000269|PubMed:27813252}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spastic paraplegia 57, autosomal recessive (SPG57) [MIM:615658]: A complicated form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. Complicated forms are recognized by additional variable features including spastic quadriparesis, seizures, dementia, amyotrophy, extrapyramidal disturbance, cerebral or cerebellar atrophy, optic atrophy, and peripheral neuropathy, as well as by extra neurological manifestations. {ECO:0000269|PubMed:23479643, ECO:0000269|PubMed:27492651, ECO:0000269|PubMed:27813252}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.247

Intolerance Scores

LoFtool: 0.391
RVIS EVS: -0.23
RVIS percentile EVS: 37.32

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.859

Gene Damage Prediction

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