MMAA

metabolism of cobalamin associated A

Basic information

Region (hg38): 4:145599041-145660033

Links

ENSG00000151611 ∙ NCBI:166785 ∙ OMIM:607481 ∙ HGNC:18871 ∙ Uniprot:Q8IVH4 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• methylmalonic aciduria, cblA type (Definitive), mode of inheritance: AR
• methylmalonic aciduria, cblA type (Definitive), mode of inheritance: AR
• methylmalonic aciduria, cblA type (Definitive), mode of inheritance: AR
• methylmalonic aciduria, cblA type (Strong), mode of inheritance: AR
• methylmalonic aciduria, cblA type (Supportive), mode of inheritance: AR
• methylmalonic aciduria, cblA type (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Methylmalonic acidemia, cblA type	AR	Biochemical	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	Biochemical; Hematologic; Neurologic; Ophthalmologic	6132336; 12438653; 20301409; 21545677; 23026888; 34652574

ClinVar

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

• Methylmalonic aciduria, cblA type (427 variants)
• not provided (44 variants)
• Methylmalonic acidemia (28 variants)
• Inborn genetic diseases (18 variants)
• not specified (14 variants)
• MMAA-related condition (4 variants)
• See cases (2 variants)
• Severe global developmental delay;Cataract;Microcephaly (1 variants)
• Methylmalonic aciduria of the cblA complementation type (1 variants)
• Methylmalonic aciduria, cblB type (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MMAA 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			1	107	2	110
missense	7	8	71	1	1	88
nonsense	17	17	2			36
start loss		1				1
frameshift	26	20	1			47
inframe indel		1	3			4
splice donor/acceptor (+/-2bp)	2	8				10
splice region		1	3	16		20
non coding			83	27	27	137
Total	52	55	161	135	30

Highest pathogenic variant AF is 0.0000263

Variants in MMAA

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

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

Position	Type	Phenotype	Significance	ClinVar
4-145619402-G-C		not specified • Methylmalonic aciduria, cblA type	Conflicting classifications of pathogenicity (Jan 12, 2018)
4-145619404-G-T		Methylmalonic aciduria, cblA type	Uncertain significance (Jan 13, 2018)
4-145619405-C-A		Methylmalonic aciduria, cblA type	Uncertain significance (Jan 13, 2018)
4-145619405-C-T		Methylmalonic aciduria, cblA type	Uncertain significance (Jan 12, 2018)
4-145619417-G-C		Methylmalonic aciduria, cblA type	Uncertain significance (Jan 13, 2018)
4-145619443-G-C			Likely benign (May 24, 2021)
4-145619459-C-T			Benign (Jun 23, 2018)
4-145627322-G-A			Uncertain significance (Sep 23, 2022)
4-145638826-A-C			Benign (Aug 07, 2018)
4-145639084-A-G		not specified • Methylmalonic aciduria, cblA type	Benign (Jun 15, 2021)
4-145639105-A-T		not specified	Benign (May 22, 2017)
4-145639126-C-T		Methylmalonic aciduria, cblA type	Conflicting classifications of pathogenicity (Feb 26, 2021)
4-145639136-G-A		Methylmalonic aciduria, cblA type • MMAA-related disorder	Likely benign (Apr 07, 2022)
4-145639140-A-G		Methylmalonic aciduria, cblA type	Likely pathogenic (May 04, 2017)
4-145639145-C-T		Methylmalonic aciduria, cblA type	Likely benign (Feb 22, 2023)
4-145639146-A-G		Methylmalonic aciduria, cblA type	Uncertain significance (Sep 26, 2022)
4-145639153-TAC-T		Methylmalonic aciduria, cblA type	Likely pathogenic (Mar 06, 2018)
4-145639154-A-G		Methylmalonic aciduria, cblA type	Likely benign (Jun 26, 2022)
4-145639160-T-C		Methylmalonic aciduria, cblA type	Likely benign (Mar 24, 2022)
4-145639172-T-C		Methylmalonic aciduria, cblA type	Likely benign (May 15, 2023)
4-145639175-C-T		Methylmalonic aciduria, cblA type	Likely benign (Jun 05, 2019)
4-145639178-A-C		Methylmalonic aciduria, cblA type	Likely benign (Sep 07, 2021)
4-145639185-C-A		Methylmalonic aciduria, cblA type	Uncertain significance (Dec 14, 2021)
4-145639189-T-A		Methylmalonic aciduria, cblA type	Likely pathogenic (May 31, 2023)
4-145639192-GA-G		Methylmalonic aciduria, cblA type	Pathogenic (Jun 15, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MMAA	protein_coding	protein_coding	ENST00000281317	6	41773

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
9.40e-13	0.0774	125633	0	114	125747	0.000453

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.331	209	223	0.938	0.0000116	2685
Missense in Polyphen		58	75.362	0.76962		881
Synonymous	0.132	80	81.5	0.981	0.00000412	845
Loss of Function	0.494	20	22.5	0.888	0.00000145	244

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000265	0.000265
Ashkenazi Jewish	0.00	0.00
East Asian	0.000272	0.000272
Finnish	0.000139	0.000139
European (Non-Finnish)	0.000715	0.000712
Middle Eastern	0.000272	0.000272
South Asian	0.000431	0.000425
Other	0.000656	0.000652

dbNSFP

Source: dbNSFP

• Function: FUNCTION: GTPase, binds and hydrolyzes GTP (PubMed:28497574, PubMed:20876572). Involved in intracellular vitamin B12 metabolism, mediates the transport of cobalamin (Cbl) into mitochondria for the final steps of adenosylcobalamin (AdoCbl) synthesis. Functions as a G-protein chaperone that assists AdoCbl cofactor delivery from MMAB to the methylmalonyl-CoA mutase (MUT) and reactivation of the enzyme during catalysis (PubMed:28497574, PubMed:20876572). {ECO:0000269|PubMed:20876572, ECO:0000269|PubMed:28497574}.
• Pathway: Metabolism of lipids;Propionyl-CoA catabolism;Mitochondrial Fatty Acid Beta-Oxidation;Cobalamin (Cbl, vitamin B12) transport and metabolism;Metabolism;Fatty acid metabolism;Metabolism of water-soluble vitamins and cofactors;Metabolism of vitamins and cofactors (Consensus)

Recessive Scores

• pRec: 0.0990

Intolerance Scores

• loftool: 0.293
• rvis_EVS: -0.69
• rvis_percentile_EVS: 15.12

Haploinsufficiency Scores

• pHI: 0.108
• hipred: N
• hipred_score: 0.414
• ghis: 0.572

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.164

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Mmaa

Gene ontology

• Biological process: cobalamin metabolic process;cobalamin biosynthetic process
• Cellular component: mitochondrial matrix
• Molecular function: GTPase activity;protein binding;GTP binding;identical protein binding;protein homodimerization activity