PEX11B

protein-coding

peroxisomal biogenesis factor 11 beta, the group of Peroxins

Gene summary

The protein encoded by this gene facilitates peroxisomal proliferation and interacts with PEX19. The encoded protein is found in the peroxisomal membrane. Several transcript variants, some protein-coding and some not protein-coding, have been found for this gene. [provided by RefSeq, Dec 2012]

MANE transcript

NM_003846.3

Inheritance

ClinVar variants

P:19U:132B:70

Top phenotype

Peroxisome biogenesis factor disorder 14B

gnomAD constraint

pLI —, LoF o/e 0.6

Max pathogenic AF

—

Genomic locus

chr1:145,911,350-145,918,717

External References & Databases

Ensembl (ENSG00000131779)

Transcript & Mutation Effects

hg38 • Region Span ~7.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

peroxisome biogenesis disorder 14BDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013967

Submitter: G2P

peroxisome biogenesis disorder 14BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013967

Submitter: Ambry Genetics

Zellweger spectrum disordersSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019609

Submitter: Orphanet

peroxisome biogenesis disorder 14BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013967

Submitter: PanelApp Australia

peroxisome biogenesis disorder 14BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013967

Submitter: Labcorp Genetics (formerly Invitae)

peroxisome biogenesis disorderDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019234

Submitter: ClinGen

The relationship between PEX11B and peroxisome biogenesis disorder (type 14B included), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of January, 2020. PEX11B encodes an integral peroxisome membrane protein involved in peroxisome elongation and division. Peroxisomal biogenesis disorders are caused by defects in various stages of peroxisomal protein import and/or peroxisome biogenesis, involving at least 14 PEX genes. The PEX11 protein family comprises three isoforms, PEX11α, PEX11β and PEX11γ, encoded by PEX11A, PEX11B and PEX11G genes, respectively (Waterham and Ebberink 2012, PMID 22871920). While PEX11A and PEX11G have not been reported in relation to PBDs in humans, a few patients with mild PBD phenotype have been described with PEX11B mutations. A common feature observed in all affected individuals has been bilateral congenital cataracts. PEX11B was first reported in relation to autosomal recessive Peroxisome biogenesis disorder in 2012. (Ebberink et al, 2012; PMID: 22581968). At least 5 nonsense or deletion variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data (7 points): Variants in this gene have been reported in at least 5 probands in 3 publications (PMID: 22581968, 28129423, 31724321). The mechanism for disease is expected to be homozygous loss of function. Summary of experimental data (4.5 points): This gene-disease association is supported by in vitro functional assays (PMIDs 22581968, 21669930, 24234511) and a mouse model (PMID: 12024045). PEX11B interacts with PEX19 (PMID: 12096124). In summary, PEX11B is definitively associated with autosomal recessive peroxisome biogenesis disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Peroxisomal Disorders GCEP on January 17, 2020 (SOP Version 7).

Clinical Genomic Database (CGD)

Peroxisome biogenesis factor disorder 14BAR

Manifestation: Biochemical; Craniofacial; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic; Renal

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: 22581968

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PEX11B variants in ClinVar

8 Conditions Cataloged

not providedTotal: 231

Inborn genetic diseasesTotal: 41

PEX11B-related disorderTotal: 39

not specifiedTotal: 27

Peroxisome biogenesis disorder 14BTotal: 19

Peroxisome biogenesis disorderTotal: 2

Radial aplasia-thrombocytopenia syndromeTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003846.3. 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			3 clinvar	66 clinvar		69
missense			128 clinvar	4 clinvar		132
nonsense	2 clinvar	5 clinvar	1 clinvar			8
start loss		2 clinvar				2
frameshift	2 clinvar	6 clinvar				8
splice donor/acceptor (+/-2bp)		2 clinvar				2
Total	4	15	132	70	0	221

Highest pathogenic variant AF is 0.000009916012

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003846.3	RefSeq	NP_003837.1	4	MANE Select
ENST00000369306.8	Ensembl	ENSP00000358312.3	4	MANE Select
NM_001184795.1	RefSeq	NP_001171724.1	4	Standard
ENST00000428634.1	Ensembl	ENSP00000414018.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Peroxisome - Homo sapiens (human)

Biological Process

peroxisome organization
signal transduction
peroxisome fission
regulation of peroxisome size
protein homooligomerization

Molecular Function

protein binding
protein homodimerization activity

Cellular Component

mitochondrion
peroxisome
peroxisomal membrane
integral component of peroxisomal membrane
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000369306
Coding exons: 4
Length: 7479
Individuals with no LoFs: 125722
Homozygous LoFs: 0
Heterozygous LoFs: 25
Defined: 125747
p: 0.0000994

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.305	156	146	1.07	0.00000837	1603
Missense (PolyPhen)		60	53.775	1.1158		638
Synonymous	0.898	49	57.7	0.850	0.00000290	596
Loss of Function	1.36	8	13.4	0.599	9.37e-7	126

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000090	0.000088	rare
South Asian	0.00013	0.00013	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in peroxisomal proliferation (PubMed:9792670). May regulate peroxisome division by recruiting the dynamin-related GTPase DNM1L to the peroxisomal membrane (PubMed:12618434). Promotes membrane protrusion and elongation on the peroxisomal surface (PubMed:20826455). {ECO:0000269|PubMed:12618434, ECO:0000269|PubMed:20826455, ECO:0000269|PubMed:9792670}.;
Disease: DISEASE: Peroxisome biogenesis disorder 14B (PBD14B) [MIM:614920]: An autosomal recessive peroxisome biogenesis disorder characterized clinically by mild intellectual disability, congenital cataracts, progressive hearing loss, and polyneuropathy. Additionally, recurrent migraine-like episodes following mental stress or physical exertion, not a common feature in peroxisome disorders, are observed. {ECO:0000269|PubMed:22581968}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.191

Intolerance Scores

LoFtool: 0.877
RVIS EVS: -0.27
RVIS percentile EVS: 33.97

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.980

Gene Damage Prediction

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