MMACHC

metabolism of cobalamin associated C

Basic information

Region (hg38): 1:45500300-45513382

Links

ENSG00000132763 ∙ NCBI:25974 ∙ OMIM:609831 ∙ HGNC:24525 ∙ Uniprot:Q9Y4U1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• methylmalonic aciduria and homocystinuria type cblC (Definitive), mode of inheritance: AR
• methylmalonic aciduria and homocystinuria type cblC (Definitive), mode of inheritance: AR
• methylmalonic aciduria and homocystinuria type cblC (Strong), mode of inheritance: AR
• methylmalonic aciduria and homocystinuria type cblC (Strong), mode of inheritance: AR
• methylmalonic aciduria and homocystinuria type cblC (Supportive), mode of inheritance: AR
• methylmalonic aciduria and homocystinuria type cblC (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Methylmalonic aciduria and homocystinuria, cblC type	AR/Digenic	Biochemical	While no treatment is completely effective, specific dietary (eg, high-calorie, low protein diet and avoidance of fasting, with measures taken to avoid/treat decompensation) and other medical measures (eg, cofactor therapy) may be beneficial to treat and prevent sequelae in the acute and chronic states	Biochemical; Cardiovascular; Dermatologic; Hematologic; Neurologic; Ophthalmologic; Renal	5779140; 6749192; 3257264; 2368803; 9266389; 11258350; 10399092; 11320193; 12210350; 16311595; 16714133; 17431913; 17853453; 20301503; 19370762; 20631720; 21748409; 21835369; 23837176; 29302025; 34652574
Compound heterozygosity and digenic inheritance (with PRDX1) has been described

ClinVar

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

• Cobalamin_C_disease (525 variants)
• not_provided (85 variants)
• Inborn_genetic_diseases (50 variants)
• Methylmalonic_acidemia_with_homocystinuria_cblC (50 variants)
• Disorders_of_Intracellular_Cobalamin_Metabolism (34 variants)
• not_specified (30 variants)
• MMACHC-related_disorder (19 variants)
• See_cases (4 variants)
• METHYLMALONIC_ACIDURIA_AND_HOMOCYSTINURIA,_cblC_TYPE,_DIGENIC (3 variants)
• Methylmalonic_aciduria_due_to_methylmalonyl-CoA_mutase_deficiency (2 variants)
• Atypical_hemolytic-uremic_syndrome (1 variants)
• cblC_type_of_combined_methylmalonic_aciduria_and_homocystinuria (1 variants)
• Methylmalonic_aciduria_and_homocystinuria (1 variants)
• Abnormality_of_metabolism/homeostasis (1 variants)
• Homocystinuria (1 variants)
• Methylmalonic_aciduria,_type_cblc (1 variants)
• Methylmalonic_aciduria (1 variants)
• Retinal_dystrophy (1 variants)
• Methylmalonic_aciduria_and_homocystinuria_type_cblD (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MMACHC gene is commonly pathogenic or not. These statistics are base on transcript: NM_000015506.3. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous	2	1	1	146	1	151
missense	8	34	136	15	1	194
nonsense	23	15	1			39
start loss	3	2				5
frameshift	37	32	13			82
splice donor/acceptor (+/-2bp)	5	9		1		15
Total	78	93	151	162	2

Highest pathogenic variant AF is 0.0010327315

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MMACHC	protein_coding	protein_coding	ENST00000401061	4	11015

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.14e-13	0.00620	124377	0	440	124817	0.00176

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-1.08	213	173	1.23	0.0000100	1801
Missense in Polyphen		64	51.284	1.248		565
Synonymous	-1.65	83	66.0	1.26	0.00000349	611
Loss of Function	-0.764	18	14.8	1.21	0.00000108	116

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00392	0.00392
Ashkenazi Jewish	0.00278	0.00278
East Asian	0.00117	0.00117
Finnish	0.0000928	0.0000928
European (Non-Finnish)	0.00193	0.00193
Middle Eastern	0.00117	0.00117
South Asian	0.00131	0.00131
Other	0.00215	0.00214

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Catalyzes the reductive dealkylation of cyanocobalamin to cob(II)alamin, using FAD or FMN as cofactor and NADPH as cosubstrate (PubMed:19700356, PubMed:21697092, PubMed:22642810). Can also catalyze the glutathione-dependent reductive demethylation of methylcobalamin, and, with much lower efficiency, the glutathione-dependent reductive demethylation of adenosylcobalamin (PubMed:19801555, PubMed:22642810, PubMed:25809485). Under anaerobic conditions cob(I)alamin is the first product; it is highly reactive and is converted to aquocob(II)alamin in the presence of oxygen (PubMed:19801555). Binds cyanocobalamin, adenosylcobalamin, methylcobalamin and other, related vitamin B12 derivatives (PubMed:21071249). {ECO:0000269|PubMed:19700356, ECO:0000269|PubMed:19801555, ECO:0000269|PubMed:21071249, ECO:0000269|PubMed:21697092, ECO:0000269|PubMed:22642810, ECO:0000269|PubMed:25809485}.
• Pathway: Vitamin digestion and absorption - Homo sapiens (human);Cobalamin (Cbl, vitamin B12) transport and metabolism;Metabolism;Metabolism of water-soluble vitamins and cofactors;Metabolism of vitamins and cofactors (Consensus)

Recessive Scores

• pRec: 0.166

Intolerance Scores

• loftool: 0.318
• rvis_EVS: -0.13
• rvis_percentile_EVS: 43.91

Haploinsufficiency Scores

• pHI: 0.0929
• hipred: N
• hipred_score: 0.167
• ghis: 0.511

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.578

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Mmachc
• Phenotype: respiratory system phenotype; embryo phenotype; hematopoietic system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; vision/eye phenotype; digestive/alimentary phenotype; renal/urinary system phenotype; homeostasis/metabolism phenotype; immune system phenotype; cellular phenotype; endocrine/exocrine gland phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); craniofacial phenotype

Zebrafish Information Network

• Gene name: mmachc
• Affected structure: ceratobranchial cartilage
• Phenotype tag: abnormal
• Phenotype quality: absent

Gene ontology

• Biological process: glutathione metabolic process;cobalamin metabolic process;cobalamin biosynthetic process;oxidation-reduction process;demethylation
• Cellular component: cytoplasm;cytosol
• Molecular function: protein binding;oxidoreductase activity;cobalamin binding;demethylase activity;cyanocobalamin reductase (cyanide-eliminating) activity;protein homodimerization activity;glutathione binding;FAD binding