FUS

FUS RNA binding protein, the group of Zinc fingers RANBP2-type |RNA binding motif containing|Heterogeneous nuclear ribonucleoproteins

Basic information

Region (hg38): 16:31180138-31196963

Previous symbols: [ "ALS6" ]

Links

ENSG00000089280 ∙ NCBI:2521 ∙ OMIM:137070 ∙ HGNC:4010 ∙ Uniprot:P35637 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• amyotrophic lateral sclerosis type 6 (Strong), mode of inheritance: AD
• amyotrophic lateral sclerosis (Definitive), mode of inheritance: AD
• amyotrophic lateral sclerosis (Supportive), mode of inheritance: AD
• juvenile amyotrophic lateral sclerosis (Supportive), mode of inheritance: AR
• tremor, hereditary essential, 4 (Limited), mode of inheritance: AD
• amyotrophic lateral sclerosis type 6 (Strong), mode of inheritance: AD
• tremor, hereditary essential, 4 (Limited), mode of inheritance: Unknown
• amyotrophic lateral sclerosis type 6 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Amyotrophic lateral sclerosis 6, with or without frontotemporal dementia; Tremor, hereditary essential, 4	AD/AR	General	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	Neurologic	12840784; 12858291; 19741216; 19251627; 19741215; 19251628; 19861302; 20385912; 20577002; 20660363; 20668259; 22863194; 22980027; 22999566; 23046859

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the FUS gene.

• Amyotrophic lateral sclerosis type 6;Tremor, hereditary essential, 4 (10 variants)
• not provided (10 variants)
• Amyotrophic lateral sclerosis type 6 (7 variants)
• Tremor, hereditary essential, 4;Amyotrophic lateral sclerosis type 6 (6 variants)
• Juvenile amyotrophic lateral sclerosis (2 variants)
• FUS-related disorder (2 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FUS gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	72	4	77
missense	8	7	113	9		137
nonsense	3	1				4
start loss						0
frameshift	12					12
inframe indel			16	5	1	22
splice donor/acceptor (+/-2bp)	2	2	3	1		8
splice region			10	16	1	27
non coding			17	63	21	101
Total	25	10	150	150	26

Highest pathogenic variant AF is 0.0000136

Variants in FUS

This is a list of pathogenic ClinVar variants found in the FUS region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
16-31180161-A-G		Amyotrophic lateral sclerosis type 6	Benign (Jul 03, 2018)
16-31180162-C-T		Amyotrophic lateral sclerosis type 6	Uncertain significance (Jan 13, 2018)
16-31180164-C-T		Amyotrophic lateral sclerosis type 6	Uncertain significance (Jan 13, 2018)
16-31180166-G-A		Amyotrophic lateral sclerosis type 6	Uncertain significance (Jan 13, 2018)
16-31180166-G-T		Amyotrophic lateral sclerosis type 6	Uncertain significance (Jan 13, 2018)
16-31180167-C-G		Amyotrophic lateral sclerosis type 6	Uncertain significance (Jan 13, 2018)
16-31180168-G-A		Amyotrophic lateral sclerosis type 6	Benign/Likely benign (Sep 08, 2020)
16-31180171-G-A			Likely benign (Nov 01, 2021)
16-31180176-A-G		Amyotrophic lateral sclerosis type 6	Benign/Likely benign (Jul 13, 2019)
16-31180200-C-G		Amyotrophic lateral sclerosis type 6	Uncertain significance (Jan 12, 2018)
16-31180209-G-C			Uncertain significance (Feb 01, 2024)
16-31180210-C-G		FUS-related disorder	Likely benign (Dec 18, 2019)
16-31180220-C-T		FUS-related disorder	Likely benign (Dec 15, 2021)
16-31180236-GGGC-G		Dystonic disorder;Myoclonus • Amyotrophic lateral sclerosis type 6	Uncertain significance (Oct 19, 2018)
16-31182389-C-G		Amyotrophic lateral sclerosis type 6;Tremor, hereditary essential, 4 • FUS-related disorder	Likely benign (Nov 02, 2022)
16-31182415-A-G		not specified	Uncertain significance (Jun 26, 2017)
16-31182441-C-T		Amyotrophic lateral sclerosis type 6;Tremor, hereditary essential, 4	Likely benign (Apr 22, 2023)
16-31182495-G-A		Amyotrophic lateral sclerosis type 6;Tremor, hereditary essential, 4	Uncertain significance (Oct 18, 2023)
16-31182501-C-T		Amyotrophic lateral sclerosis type 6	Uncertain significance (Jan 13, 2018)
16-31182502-C-G		Tremor, hereditary essential, 4;Amyotrophic lateral sclerosis type 6	Likely benign (Sep 01, 2021)
16-31182514-T-A		Amyotrophic lateral sclerosis type 6	Uncertain significance (Mar 16, 2018)
16-31182515-A-G		FUS-related disorder	Uncertain significance (Oct 03, 2022)
16-31182521-C-T		Amyotrophic lateral sclerosis type 6;Tremor, hereditary essential, 4 • Inborn genetic diseases • FUS-related disorder	Likely benign (Nov 04, 2022)
16-31182526-C-A		Amyotrophic lateral sclerosis type 6;Tremor, hereditary essential, 4	Likely benign (Sep 08, 2023)
16-31182526-C-T		Amyotrophic lateral sclerosis type 6 • Amyotrophic lateral sclerosis type 6;Tremor, hereditary essential, 4 • FUS-related disorder	Uncertain significance (Jul 30, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FUS	protein_coding	protein_coding	ENST00000254108	15	11697

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.999	0.000695	125728	0	5	125733	0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.21	217	330	0.658	0.0000207	3400
Missense in Polyphen		28	63.684	0.43967		648
Synonymous	-2.13	147	118	1.25	0.00000745	1027
Loss of Function	5.16	4	38.6	0.104	0.00000228	381

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000591	0.0000591
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000177	0.0000176
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.000165	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Binds both single-stranded and double-stranded DNA and promotes ATP-independent annealing of complementary single- stranded DNAs and D-loop formation in superhelical double-stranded DNA. May play a role in maintenance of genomic integrity.
• Disease: DISEASE: Note=A chromosomal aberration involving FUS is found in a patient with malignant myxoid liposarcoma. Translocation t(12;16)(q13;p11) with DDIT3. {ECO:0000269|PubMed:7503811}.; DISEASE: Note=A chromosomal aberration involving FUS is a cause of acute myeloid leukemia (AML). Translocation t(16;21)(p11;q22) with ERG. {ECO:0000269|PubMed:8187069}.; DISEASE: Angiomatoid fibrous histiocytoma (AFH) [MIM:612160]: A distinct variant of malignant fibrous histiocytoma that typically occurs in children and adolescents and is manifest by nodular subcutaneous growth. Characteristic microscopic features include lobulated sheets of histiocyte-like cells intimately associated with areas of hemorrhage and cystic pseudovascular spaces, as well as a striking cuffing of inflammatory cells, mimicking a lymph node metastasis. {ECO:0000269|PubMed:11063792}. Note=The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration involving FUS is found in a patient with angiomatoid fibrous histiocytoma. Translocation t(12;16)(q13;p11.2) with ATF1 generates a chimeric FUS/ATF1 protein. {ECO:0000269|PubMed:11063792}.; DISEASE: Amyotrophic lateral sclerosis 6, with or without frontotemporal dementia (ALS6) [MIM:608030]: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. {ECO:0000269|PubMed:19251627, ECO:0000269|PubMed:19251628, ECO:0000269|PubMed:19861302, ECO:0000269|PubMed:20124201, ECO:0000269|PubMed:27604643}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Tremor, hereditary essential 4 (ETM4) [MIM:614782]: A common movement disorder mainly characterized by postural tremor of the arms. Head, legs, trunk, voice, jaw, and facial muscles also may be involved. The condition can be aggravated by emotions, hunger, fatigue and temperature extremes, and may cause a functional disability or even incapacitation. Inheritance is autosomal dominant. {ECO:0000269|PubMed:22863194}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Transcriptional misregulation in cancer - Homo sapiens (human);mRNA Processing;Metabolism of RNA;mRNA Splicing - Major Pathway;mRNA Splicing;Processing of Capped Intron-Containing Pre-mRNA (Consensus)

Recessive Scores

• pRec: 0.491

Intolerance Scores

• loftool: 0.00503
• rvis_EVS: -1
• rvis_percentile_EVS: 8.32

Haploinsufficiency Scores

• pHI: 0.426
• hipred: Y
• hipred_score: 0.775
• ghis: 0.679

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.856

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Fus
• Phenotype: endocrine/exocrine gland phenotype; growth/size/body region phenotype; cellular phenotype; immune system phenotype; homeostasis/metabolism phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: fus
• Affected structure: CaP motoneuron
• Phenotype tag: abnormal
• Phenotype quality: decreased length

Gene ontology

• Biological process: mRNA splicing, via spliceosome;regulation of transcription, DNA-templated;cellular response to calcium ion;positive regulation of nucleic acid-templated transcription
• Cellular component: nucleus;nucleoplasm;polysome;perikaryon;dendritic spine head;perinuclear region of cytoplasm
• Molecular function: DNA binding;transcription coactivator activity;RNA binding;protein binding;estrogen receptor binding;myosin V binding;ionotropic glutamate receptor binding;identical protein binding;metal ion binding;retinoid X receptor binding;thyroid hormone receptor binding