PEX6

peroxisomal biogenesis factor 6, the group of Peroxins|AAA ATPases

Basic information

Region (hg38): 6:42963865-42979181

Links

ENSG00000124587 ∙ NCBI:5190 ∙ OMIM:601498 ∙ HGNC:8859 ∙ Uniprot:Q13608 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• peroxisome biogenesis disorder 4A (Zellweger) (Definitive), mode of inheritance: AR
• peroxisome biogenesis disorder 4A (Zellweger) (Definitive), mode of inheritance: AR
• Zellweger spectrum disorders (Supportive), mode of inheritance: AR
• autosomal recessive cerebellar ataxia-blindness-deafness syndrome (Supportive), mode of inheritance: AR
• peroxisome biogenesis disorder 4B (Definitive), mode of inheritance: AR
• peroxisome biogenesis disorder 4A (Zellweger) (Strong), mode of inheritance: AR
• peroxisome biogenesis disorder (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Heimler syndrome 2 (Peroxisome biogenesis disorder 4C)	AR	Audiologic/Otolaryngologic	Heimler syndrome 2, representing a mild peroxisomal biogenesis disorder, includes sensorineural hearing loss among other features, and early recognition and treatment of hearing impairment may improve outcomes, including speech and language development	Audiologic/Otolaryngologic; Biochemical; Craniofacial; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic; Renal	8940266; 8670792; 10408779; 11355018; 16530715; 17041890; 19877282; 21937992; 22894767; 26387595

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PEX6 gene.

• Peroxisome biogenesis disorder (91 variants)
• Heimler syndrome 2 (18 variants)
• Peroxisome biogenesis disorder 4A (Zellweger) (7 variants)
• not provided (6 variants)
• Zellweger spectrum disorders (4 variants)
• Peroxisome biogenesis disorder 4B (3 variants)
• Peroxisome biogenesis disorder 4A (Zellweger);Peroxisome biogenesis disorder 4B (2 variants)
• PEX6-related disorder (1 variants)
• Heimler syndrome 2;Peroxisome biogenesis disorder 4A (Zellweger);Peroxisome biogenesis disorder 4B (1 variants)
• Peroxisome biogenesis disorder 4B;Peroxisome biogenesis disorder 4A (Zellweger) (1 variants)
• Heimler syndrome 2;Peroxisome biogenesis disorder 4B;Peroxisome biogenesis disorder 4A (Zellweger) (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PEX6 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			11	515	3	529
missense	8	12	467	29	2	518
nonsense	26	27	1			54
start loss	3	1				4
frameshift	57	74	2	2		135
inframe indel	1	2	14			17
splice donor/acceptor (+/-2bp)	6	35	1			42
splice region			24	67	1	92
non coding			7	206	22	235
Total	101	151	503	752	27

Highest pathogenic variant AF is 0.0000396

Variants in PEX6

This is a list of pathogenic ClinVar variants found in the PEX6 region.

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

Position	Type	Phenotype	Significance	ClinVar
6-42963889-GTTTA-G		Peroxisome biogenesis disorder 1A (Zellweger) • Peroxisome biogenesis disorder • PEX6 POLYMORPHISM • not specified	Conflicting classifications of pathogenicity (Jan 13, 2023)
6-42963928-A-C		Peroxisome biogenesis disorder 4A (Zellweger)	Uncertain significance (Jan 13, 2018)
6-42963967-C-T		Peroxisome biogenesis disorder 4A (Zellweger)	Uncertain significance (Jan 13, 2018)
6-42963992-C-G		Peroxisome biogenesis disorder 4A (Zellweger)	Uncertain significance (Jan 13, 2018)
6-42964016-G-A		Peroxisome biogenesis disorder 4A (Zellweger)	Benign (Oct 17, 2018)
6-42964123-G-A		Peroxisome biogenesis disorder 4A (Zellweger)	Likely benign (Mar 10, 2019)
6-42964153-A-AT			Likely benign (Sep 20, 2020)
6-42964167-G-A		Peroxisome biogenesis disorder 4A (Zellweger)	Uncertain significance (Jan 12, 2018)
6-42964335-C-T		Peroxisome biogenesis disorder	Likely benign (May 08, 2022)
6-42964340-A-C		Peroxisome biogenesis disorder	Uncertain significance (Oct 17, 2022)
6-42964340-A-T		Peroxisome biogenesis disorder	Uncertain significance (Aug 31, 2021)
6-42964342-G-A		not specified • Peroxisome biogenesis disorder 4A (Zellweger) • Peroxisome biogenesis disorder • Zellweger spectrum disorders	Benign/Likely benign (Jan 31, 2024)
6-42964350-C-T		Peroxisome biogenesis disorder	Likely benign (Jan 27, 2024)
6-42964354-C-A		Peroxisome biogenesis disorder • Zellweger spectrum disorders • PEX6-related disorder	Uncertain significance (Dec 11, 2023)
6-42964354-C-T		PEX6-related disorder	Uncertain significance (May 28, 2024)
6-42964355-G-A		Peroxisome biogenesis disorder	Uncertain significance (Feb 15, 2023)
6-42964357-T-G		Peroxisome biogenesis disorder	Uncertain significance (Sep 17, 2021)
6-42964363-C-A		Peroxisome biogenesis disorder	Uncertain significance (Mar 26, 2020)
6-42964363-C-T		Peroxisome biogenesis disorder	Uncertain significance (Nov 28, 2021)
6-42964364-G-A		Peroxisome biogenesis disorder	Uncertain significance (Jun 27, 2022)
6-42964365-C-G		Peroxisome biogenesis disorder	Uncertain significance (Aug 01, 2022)
6-42964368-G-A		Peroxisome biogenesis disorder	Likely benign (Dec 01, 2023)
6-42964370-A-G		Peroxisome biogenesis disorder • Inborn genetic diseases	Uncertain significance (Apr 25, 2023)
6-42964371-C-G		Peroxisome biogenesis disorder 4A (Zellweger) • Peroxisome biogenesis disorder • Zellweger spectrum disorders	Conflicting classifications of pathogenicity (Feb 01, 2024)
6-42964371-C-T		Peroxisome biogenesis disorder	Likely benign (Oct 21, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PEX6	protein_coding	protein_coding	ENST00000304611	17	15351

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00000625	1.00	125617	0	131	125748	0.000521

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.44	436	529	0.824	0.0000311	6093
Missense in Polyphen		139	183.72	0.75659		2149
Synonymous	0.362	220	227	0.969	0.0000120	2268
Loss of Function	3.21	15	35.7	0.421	0.00000167	443

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000478	0.000478
Ashkenazi Jewish	0.00	0.00
East Asian	0.000381	0.000381
Finnish	0.000451	0.000323
European (Non-Finnish)	0.000637	0.000633
Middle Eastern	0.000381	0.000381
South Asian	0.00105	0.00105
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Involved in peroxisome biosynthesis. Required for stability of the PTS1 receptor. Anchored by PEX26 to peroxisome membranes, possibly to form heteromeric AAA ATPase complexes required for the import of proteins into peroxisomes.
• Disease: DISEASE: Peroxisome biogenesis disorder 4A (PBD4A) [MIM:614862]: A fatal peroxisome biogenesis disorder belonging to the Zellweger disease spectrum and clinically characterized by severe neurologic dysfunction with profound psychomotor retardation, severe hypotonia and neonatal seizures, craniofacial abnormalities, liver dysfunction, and biochemically by the absence of peroxisomes. Additional features include cardiovascular and skeletal defects, renal cysts, ocular abnormalities, and hearing impairment. Most severely affected individuals with the classic form of the disease (classic Zellweger syndrome) die within the first year of life. {ECO:0000269|PubMed:10408779, ECO:0000269|PubMed:8670792}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Peroxisome biogenesis disorder 4B (PBD4B) [MIM:614863]: A peroxisome biogenesis disorder that includes neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD), two milder manifestations of the Zellweger disease spectrum. The clinical course of patients with the NALD and IRD presentation is variable and may include developmental delay, hypotonia, liver dysfunction, sensorineural hearing loss, retinal dystrophy and vision impairment. Children with the NALD presentation may reach their teens, while patients with the IRD presentation may reach adulthood. The clinical conditions are often slowly progressive in particular with respect to loss of hearing and vision. The biochemical abnormalities include accumulation of phytanic acid, very long chain fatty acids (VLCFA), di- and trihydroxycholestanoic acid and pipecolic acid. {ECO:0000269|PubMed:11355018}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Heimler syndrome 2 (HMLR2) [MIM:616617]: A form of Heimler syndrome, a very mild peroxisome biogenesis disorder characterized by sensorineural hearing loss, amelogenesis imperfecta resulting in enamel hyoplasia of the secondary dentition, nail defects, and occasional or late-onset retinal pigmentation abnormalities. {ECO:0000269|PubMed:19105186, ECO:0000269|PubMed:26387595, ECO:0000269|PubMed:27302843}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Peroxisome - Homo sapiens (human);Metabolism of proteins;Peroxisomal protein import (Consensus)

Recessive Scores

• pRec: 0.206

Intolerance Scores

• loftool: 0.114
• rvis_EVS: 1.14
• rvis_percentile_EVS: 92.34

Haploinsufficiency Scores

• pHI: 0.366
• hipred: N
• hipred_score: 0.477
• ghis: 0.422

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.452

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Pex6

Gene ontology

• Biological process: protein targeting to peroxisome;peroxisome organization;protein import into peroxisome matrix;protein import into peroxisome matrix, translocation;protein stabilization
• Cellular component: photoreceptor outer segment;cytoplasm;peroxisome;peroxisomal membrane;cytosol;photoreceptor cell cilium
• Molecular function: protein binding;ATP binding;protein C-terminus binding;ATPase activity;ATPase activity, coupled;protein-containing complex binding