GeneBe

MMAB

protein-coding

metabolism of cobalamin associated B, the group of Cilia and flagella associated

Gene summary

This gene encodes a protein that catalyzes the final step in the conversion of vitamin B(12) into adenosylcobalamin (AdoCbl), a vitamin B12-containing coenzyme for methylmalonyl-CoA mutase. Mutations in the gene are the cause of vitamin B12-dependent methylmalonic aciduria linked to the cblB complementation group. Alternatively spliced transcript variants have been found. [provided by RefSeq, Apr 2011]

MANE transcript

NM_052845.4

Inheritance

AR

ClinVar variants

P:116U:107B:139

Top phenotype

Methylmalonic acidemia, cblB type

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr12:109,553,715-109,573,580

External References & Databases

Ensembl (ENSG00000139428)NCBI Gene (326625)OMIM (607568)HGNC:19331GenCCUniProt (Q96EY8)AlphaFoldClinVar (MMAB)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~19.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

methylmalonic aciduria, cblB typeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009614

Submitter: Natera

methylmalonic aciduria, cblB typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009614

Submitter: PanelApp Australia

methylmalonic aciduria, cblB typeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009614

Submitter: G2P

methylmalonic aciduria, cblB typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009614

Submitter: Labcorp Genetics (formerly Invitae)

methylmalonic aciduria, cblB typeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009614

Submitter: Myriad Women's Health

methylmalonic aciduria, cblB typeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009614

Submitter: Orphanet

methylmalonic aciduria, cblB typeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009614

Submitter: ClinGen

The relationship between MMAB and methylmalonic aciduria, cblB type, was evaluated using the ClinGen Clinical Validity Framework as of January 22, 2021. Loss of function of the MMAB gene product, ATP:cob(I)alamin adenosyltransferase (ATR), has been reported to methylmalonic aciduria (MMA), CblB type, based on complementation studies. The severe, early-onset form of this condition presents with neonatal ketoacidosis, lethargy, failure to thrive and encephalopathy. Patients with a milder form are usually diagnosed during infancy and have less severe neurological symptoms (Brasil et al, 2015). While patients with MMA due to variants in MMAA (type CblA) are responsive to Vitamin B12, only rare individuals with type CblB are responsive to treatment with Vitamin B12 (Hörster, et al, 2007, PMID 17597648; Manoli et al, 2016, PMID 20301409). Biallelic variants in MMAB were first reported in humans with methylmalonic aciduria, cblB type, in 2002 (Dobson et al, PMID 12471062). Since then, over 30 different variants have been associated with the condition (Brasil et al, 2015, PMID 24813872; https://databases.lovd.nl/shared/variants/MMAB/unique ). Evidence supporting this gene-disease relationship includes case-level and experimental data. Ten unique variants (nonsense, frameshift, splice site, missense) from 8 probands from 3 publications were curated (Dobson et al, 2002, PMID 12471062; Lerner-Ellis et al, 2006, PMID 16410054; Brasil et al, 2015, PMID 24813872). Further evidence is available in the literature but the maximum score for genetic evidence (12 points) has been reached. The gene-disease relationship is also supported by the biochemical function of ATR, which converts reduced cob(I)alamin to adenosylcobalamin (AdoCbl), the cofactor of methylmalonyl-CoA mutase (MUT) (Leal et al, 2003, PMID 12514191; Yamanishi et al, 2005, PMID 15950874; Mera and Escalante-Semerena, 2010, PMID 20677021). MUT catalyzes the reversible rearrangement of methylmalonyl-CoA to succinyl-CoA during the catabolism of branched-chain amino acids, odd-chain fatty acids and cholesterol. Lack of AdoCbl is therefore expected to result in reduced MUT activity, and methylmalonic acidemia. Of note, other defects in cobalamin metabolism can affect the activity of methionine synthase in addition to MUT, thus causing both homocystinuria and MMA. The relationship between MMAB and MMA is also supported by functional alteration studies. Mutagenesis of human MMAB and expression of the variants in a bacterial system revealed missense variants that reduce ATR activity and AdoCbl binding (Fan and Bobik, 2008, PMID, 18251506). In summary, MMAB is definitively associated with methylmalonic aciduria, cblB type.. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Clinical Genomic Database (CGD)

Methylmalonic acidemia, cblB typeAR

Manifestation: Biochemical; Hematologic; Neurologic; Ophthalmologic

Intervention: Biochemical

Rationale: Long-term dietary (high-calorie diet low in propiogenic amino acid precursors with carnitine supplementation) and medical management (eg, IM hydroxocobalamin, antibiotics to decrease propionate production) is indicated; Fasting and high-protein consumption should be avoided; In the emergent setting, prompt recognition and appropriate metabolic care may be beneficial to decrease morbidity and mortality; Antioxidants for optic nerve atrophy may be beneficial; Liver/kidney transplant has been described in methylmalonic acidemia

Refs: 7213387; 12471062; 16410054; 20301409; 20301503; 20556797; 21416195; 24813872Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MMAB variants in ClinVar

9 Conditions Cataloged
Methylmalonic aciduria, cblB typeTotal: 447
not providedTotal: 52
Inborn genetic diseasesTotal: 36
not specifiedTotal: 28
MMAB-related disorderTotal: 18
Methylmalonic acidemiaTotal: 13
Methylmalonic aciduriaTotal: 1
Hyperimmunoglobulin D with periodic feverTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_052845.4. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
129
clinvar
 130
missense
7
clinvar
21
clinvar
100
clinvar
10
clinvar
 138
nonsense
15
clinvar
7
clinvar
1
clinvar
 23
start loss
2
clinvar
2
clinvar
 4
frameshift
21
clinvar
17
clinvar
2
clinvar
 40
splice donor/acceptor (+/-2bp)
7
clinvar
17
clinvar
3
clinvar
 27
Total52641071390362

Highest pathogenic variant AF is 0.00026542792

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 52 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_052845.4RefSeqNP_443077.19MANE Select
ENST00000545712.7EnsemblENSP00000445920.19MANE Select
ENST00000420167.6EnsemblENSP00000416136.23Standard
ENST00000503497.7EnsemblENSP00000474881.14Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Porphyrin and chlorophyll metabolism - Homo sapiens (human)
  • Vitamin B12 Metabolism
  • Cobalamin (Cbl, vitamin B12) transport and metabolism
  • Metabolism
  • Metabolism of water-soluble vitamins and cofactors

Biological Process

  • cobalamin metabolic process
  • cobalamin biosynthetic process

Molecular Function

  • protein binding
  • ATP binding
  • cob(I)yrinic acid a,c-diamide adenosyltransferase activity
  • cobalamin binding

Cellular Component

  • mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000545712
Coding exons
9
Length
20138
Individuals with no LoFs
125713
Homozygous LoFs
0
Heterozygous LoFs
35
Defined
125748
p
0.000139
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.1091521481.030.000009481588
Missense (PolyPhen)4146.2610.88628504
Synonymous-0.4547166.31.070.00000490501
Loss of Function1.88613.40.4475.86e-7170

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000200.00012rare
Latino/Admixed American0.000210.00012rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.000150.00014rare
South Asian0.000390.00036rare
Other0.000690.00033rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Adenosyltransferase involved in intracellular vitamin B12 metabolism. Generates adenosylcobalamin (AdoCbl) and directly delivers the cofactor to MUT in a transfer taht is stimulated by ATP-binding to MMAB and gated by MMAA. {ECO:0000305|PubMed:28497574}.;

Recessive Scores

pRec
0.223

Intolerance Scores

LoFtool
0.271
RVIS EVS
0.33
RVIS percentile EVS
73.41

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.862

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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