MANBA

protein-coding

mannosidase beta, the group of Mannosidases type beta

Gene summary

This gene encodes a member of the glycosyl hydrolase 2 family. The encoded protein localizes to the lysosome where it is the final exoglycosidase in the pathway for N-linked glycoprotein oligosaccharide catabolism. Mutations in this gene are associated with beta-mannosidosis, a lysosomal storage disease that has a wide spectrum of neurological involvement. [provided by RefSeq, Jul 2008]

MANE transcript

NM_005908.4

Inheritance

AR, AD

ClinVar variants

P:121U:248B:257

Top phenotype

Mannosidosis, beta A, lysosomal

gnomAD constraint

pLI —, LoF o/e 0.73

Max pathogenic AF

—

Genomic locus

chr4:102,630,770-102,760,994

External References & Databases

Ensembl (ENSG00000109323)

Transcript & Mutation Effects

hg38 • Region Span ~130.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

beta-mannosidosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009562

Submitter: ClinGen

The relationship between the MANBA gene and beta-mannosidosis (MANSB), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of July 25, 2022. MANBA encodes beta-mannosidase, a lysosomal enzyme involved in the degradation of N-linked oligosaccharide moieties of glycoproteins via catalyzing the cleavage of the beta-mannoside linkage of Man-(β 1→4)GlcNAc (PMID: 9384606). Among patients with beta-mannosidosis (MANSB), beta-mannosidase deficiency results in the characteristic disease manifestation of accumulation of undegraded Man-(β 1→4)GlcNAc in multiple tissues (PMID: 2317928, PMID: 3128685). The disease mechanism of MANSB is loss of function. MANSB was first reported in 1986 by Wenger (PMID: 2945113) and Cooper (PMID: 3762648) and the first report of biallelic variants in MANBA among MANSB patients in 1998 by Alkhayat (PMID: 9384606). Both case-level (genetic) and experimental evidence support the relationship between ABHD5 and CDS. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants (PMID: 9384606, PMID: 16401745, PMID: 12468273, PMID: 18565776, PMID: 12890191, PMID: 17420068, PMID: 16904924). In total, twelve variants from eight probands in seven publications were curated. Although there is additional published case-level evidence available, the maximum score for genetic evidence (12 points) has already been reached. Experimental evidence for the relationship between MANBA and MANSB includes: the biochemical function of the gene product (beta-mannosidase) being consistent with the clinical and biochemical findings identified individuals with MANSB (PMID: 9384606, PMID: 2317928, PMID: 3128685); the biochemical and clinical features of MANBA knockout animal models (PMID: 8921369); and rescue of beta-mannosidase enzyme function via allogeneic hematopoietic cell transplantation in a patient with MANSB (PMID: 31115173). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached. In sum, MANBA is definitively associated with MANSB. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Lysosomal Diseases GCEP on August 2, 2022 (SOP v9).

beta-mannosidosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009562

Submitter: Genomics England PanelApp

beta-mannosidosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009562

Submitter: Labcorp Genetics (formerly Invitae)

beta-mannosidosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009562

Submitter: G2P

congenital nystagmusMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0005712

Submitter: PanelApp Australia

beta-mannosidosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009562

Submitter: Ambry Genetics

beta-mannosidosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009562

Submitter: PanelApp Australia

beta-mannosidosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009562

Submitter: Orphanet

Clinical Genomic Database (CGD)

Mannosidosis, beta A, lysosomalAR

Manifestation: Biochemical; 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: 3762648; 2945113; 2079835; 1623631; 1499588; 8285582; 59034; 9384606; 12468273; 16401745; 17420068; 18565776; 19728872; 22369051

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MANBA variants in ClinVar

8 Conditions Cataloged

Beta-D-mannosidosisTotal: 679

not providedTotal: 114

Inborn genetic diseasesTotal: 106

not specifiedTotal: 62

MANBA-related disorderTotal: 42

Intellectual disabilityTotal: 6

Meniere diseaseTotal: 4

Hearing impairmentTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005908.4. 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	1 clinvar		1 clinvar	234 clinvar	2 clinvar	238
missense	1 clinvar	7 clinvar	239 clinvar	20 clinvar	1 clinvar	268
nonsense	27 clinvar	14 clinvar	1 clinvar			42
start loss			1 clinvar			1
frameshift	28 clinvar	15 clinvar	3 clinvar			46
splice donor/acceptor (+/-2bp)	5 clinvar	23 clinvar	3 clinvar			31
Total	62	59	248	254	3	626

Highest pathogenic variant AF is 0.00035274005

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 64 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005908.4	RefSeq	NP_005899.3	17	MANE Select
ENST00000647097.2	Ensembl	ENSP00000495247.1	17	MANE Select
ENST00000505239.1	Ensembl	ENSP00000427322.1	16	Standard
ENST00000505239.2	Ensembl	ENSP00000427322.1	16	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
manba	Danio rerio	Structure: pericardium Quality: edematous abnormal

Gene / Model

Organism

Observed Phenotype

manba

Danio rerio

Structure: pericardium

Quality: edematous

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysosome - Homo sapiens (human)
Other glycan degradation - Homo sapiens (human)
Neutrophil degranulation
Lysosomal oligosaccharide catabolism
Metabolism of carbohydrates

Biological Process

cellular protein modification process
glycoprotein catabolic process
oligosaccharide catabolic process
neutrophil degranulation
mannan catabolic process

Molecular Function

beta-mannosidase activity
mannose binding

Cellular Component

lysosome
plasma membrane
azurophil granule membrane
lysosomal lumen
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000226578
Coding exons: 17
Length: 129492
Individuals with no LoFs: 125636
Homozygous LoFs: 0
Heterozygous LoFs: 112
Defined: 125748
p: 0.000445

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0496	468	471	0.994	0.0000250	5801
Missense (PolyPhen)		139	155.82	0.89206		1972
Synonymous	0.364	167	173	0.965	0.00000952	1609
Loss of Function	1.75	35	48.1	0.728	0.00000229	552

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00049	0.00049	rare
Latino/Admixed American	0.00032	0.00032	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00027	0.00027	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00061	0.00061	rare
South Asian	0.00036	0.00036	rare
Other	0.00082	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Exoglycosidase that cleaves the single beta-linked mannose residue from the non-reducing end of all N-linked glycoprotein oligosaccharides.;
Disease: DISEASE: Mannosidosis, beta A, lysosomal (MANSB) [MIM:248510]: An autosomal recessive lysosomal storage disease of glycoprotein catabolism. Clinical features are heterogeneous with a wide range of symptoms and age of onset. The disease is associated with a range of neurological involvement, including various degrees of mental retardation in most of the cases, hearing loss and speech impairment, hypotonia, epilepsy and peripheral neuropathy. Affected individuals have a profound reduction in beta A mannosidase activity in plasma, fibroblasts and leukocytes. {ECO:0000269|PubMed:9384606}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.331

Intolerance Scores

LoFtool: 0.513
RVIS EVS: -0.62
RVIS percentile EVS: 17.47

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.252

Gene Damage Prediction

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