FBXL4

F-box and leucine rich repeat protein 4, the group of F-box and leucine rich repeat proteins

Basic information

Region (hg38): 6:98868535-98948006

Links

ENSG00000112234 ∙ NCBI:26235 ∙ OMIM:605654 ∙ HGNC:13601 ∙ Uniprot:Q9UKA2 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• mitochondrial DNA depletion syndrome 13 (Supportive), mode of inheritance: AR
• Leigh syndrome (Definitive), mode of inheritance: AR
• mitochondrial DNA depletion syndrome 13 (Strong), mode of inheritance: AR
• mitochondrial DNA depletion syndrome 13 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Mitochondrial DNA depletion syndrome 13	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	Biochemical; Craniofacial; Neurologic; Ophthalmologic	23993193; 23993194

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the FBXL4 gene.

• Mitochondrial DNA depletion syndrome 13 (19 variants)
• not provided (11 variants)
• Inborn genetic diseases (4 variants)
• Mitochondrial DNA depletion syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FBXL4 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			45	36	4	85
missense		23	253		1	277
nonsense	11	9				20
start loss			1			1
frameshift	9	9	2			20
inframe indel		2	1			3
splice donor/acceptor (+/-2bp)	2	2				4
splice region	2	1	10	5		18
non coding			21	27	13	61
Total	22	45	323	63	18

Highest pathogenic variant AF is 0.000144

Variants in FBXL4

This is a list of pathogenic ClinVar variants found in the FBXL4 region.

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

Position	Type	Phenotype	Significance	ClinVar
6-98874188-C-G			Likely benign (Nov 09, 2018)
6-98874260-T-C		Mitochondrial DNA depletion syndrome 13	Uncertain significance (Aug 10, 2017)
6-98874267-C-T		Mitochondrial DNA depletion syndrome 13	Uncertain significance (Aug 10, 2017)
6-98874269-T-C		Mitochondrial DNA depletion syndrome 13	Conflicting classifications of pathogenicity (May 23, 2023)
6-98874273-T-C		Mitochondrial DNA depletion syndrome 13 • FBXL4-related disorder	Benign (Feb 04, 2020)
6-98874273-TTA-CTG		Mitochondrial DNA depletion syndrome 13	Uncertain significance (Aug 10, 2017)
6-98874274-T-C		Mitochondrial DNA depletion syndrome 13	Uncertain significance (Aug 10, 2017)
6-98874275-A-G		not specified • Mitochondrial DNA depletion syndrome 13	Benign (Nov 22, 2023)
6-98874285-G-C		Mitochondrial DNA depletion syndrome 13	Uncertain significance (Aug 10, 2017)
6-98874290-GCT-G			Uncertain significance (Jun 13, 2022)
6-98874298-T-C			Uncertain significance (Mar 29, 2022)
6-98874306-A-T		Mitochondrial DNA depletion syndrome 13	Likely pathogenic (Aug 10, 2017)
6-98874307-C-G		Inborn genetic diseases	Uncertain significance (Feb 17, 2023)
6-98874307-CT-C		Mitochondrial DNA depletion syndrome 13	Likely pathogenic (Aug 10, 2017)
6-98874313-G-C			Uncertain significance (Aug 27, 2021)
6-98874318-C-T		Mitochondrial DNA depletion syndrome 13	Uncertain significance (Aug 01, 2022)
6-98874348-T-C		Mitochondrial DNA depletion syndrome 13	Uncertain significance (Aug 10, 2017)
6-98874354-T-G		Mitochondrial DNA depletion syndrome 13 • not specified	Conflicting classifications of pathogenicity (Mar 08, 2024)
6-98874356-C-A		Mitochondrial DNA depletion syndrome 13	Uncertain significance (Aug 10, 2017)
6-98874356-C-T		Mitochondrial DNA depletion syndrome 13	Conflicting classifications of pathogenicity (May 28, 2022)
6-98874356-CG-C		Mitochondrial DNA depletion syndrome 13	Likely pathogenic (Feb 15, 2022)
6-98874357-G-A		Mitochondrial DNA depletion syndrome 13	Uncertain significance (Aug 20, 2022)
6-98874360-C-G		Mitochondrial DNA depletion syndrome 13	Uncertain significance (Aug 31, 2022)
6-98874365-G-A		Mitochondrial DNA depletion syndrome 13	Uncertain significance (Aug 10, 2017)
6-98874366-G-C		Mitochondrial DNA depletion syndrome 13	Uncertain significance (Aug 10, 2017)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FBXL4	protein_coding	protein_coding	ENST00000369244	7	79430

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.14e-8	0.934	125660	0	86	125746	0.000342

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.555	299	327	0.914	0.0000161	4073
Missense in Polyphen		82	105.55	0.77691		1258
Synonymous	-0.101	123	122	1.01	0.00000601	1218
Loss of Function	1.90	17	27.8	0.612	0.00000159	315

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00103	0.00102
Ashkenazi Jewish	0.000298	0.000298
East Asian	0.000381	0.000381
Finnish	0.00	0.00
European (Non-Finnish)	0.000407	0.000404
Middle Eastern	0.000381	0.000381
South Asian	0.0000980	0.0000980
Other	0.000164	0.000163

dbNSFP

Source: dbNSFP

• Pathway: Post-translational protein modification;Metabolism of proteins;Immune System;Adaptive Immune System;Antigen processing: Ubiquitination & Proteasome degradation;Class I MHC mediated antigen processing & presentation;Neddylation (Consensus)

Recessive Scores

• pRec: 0.0992

Intolerance Scores

• loftool: 0.662
• rvis_EVS: -0.93
• rvis_percentile_EVS: 9.55

Haploinsufficiency Scores

• pHI: 0.429
• hipred: N
• hipred_score: 0.414
• ghis: 0.606

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.647

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Fbxl4

Gene ontology

• Biological process: protein polyubiquitination;ubiquitin-dependent protein catabolic process;SCF-dependent proteasomal ubiquitin-dependent protein catabolic process;post-translational protein modification
• Cellular component: ubiquitin ligase complex;mitochondrial intermembrane space;cytosol;nuclear speck;SCF ubiquitin ligase complex
• Molecular function: ubiquitin-protein transferase activity