MMADHC

metabolism of cobalamin associated D

Basic information

Region (hg38): 2:149569637-149587778

Previous symbols: [ "C2orf25" ]

Links

ENSG00000168288 ∙ NCBI:27249 ∙ OMIM:611935 ∙ HGNC:25221 ∙ Uniprot:Q9H3L0 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• methylmalonic aciduria and homocystinuria type cblD (Definitive), mode of inheritance: AR
• methylmalonic aciduria and homocystinuria type cblD (Moderate), mode of inheritance: AR
• methylmalonic aciduria and homocystinuria type cblD (Strong), mode of inheritance: AR
• methylmalonic aciduria and homocystinuria type cblD (Supportive), mode of inheritance: AR
• inborn disorder of cobalamin metabolism and transport (Definitive), mode of inheritance: AR
• inborn disorder of cobalamin metabolism and transport (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Methylmalonic aciduria and homocystinuria, cblD type; Methylmalonic aciduria, cblD type	AR	Biochemical	In Homocystinuria-megaloblastic anemia, cblD type, medical management (eg, with betaine, folic acid, and OH-cobalamin) has been described as beneficial; In Methylmalonic aciduria, cblD type, B12 therapy has been reported as beneficial	Biochemical; Hematologic; Neurologic; Ophthalmologic	5524089; 2339678; 15292234; 18385497; 20301409; 20301503; 22156578; 35337626

ClinVar

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

• Methylmalonic_aciduria_and_homocystinuria_type_cblD (327 variants)
• not_provided (38 variants)
• Disorders_of_Intracellular_Cobalamin_Metabolism (24 variants)
• Inborn_genetic_diseases (24 variants)
• not_specified (15 variants)
• MMADHC-related_disorder (8 variants)
• Cobalamin_C_disease (6 variants)
• Homocystinuria-megaloblastic_anemia_cblD_type (3 variants)
• Isolated_methylmalonic_aciduria_cblD_type (3 variants)
• See_cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MMADHC gene is commonly pathogenic or not. These statistics are base on transcript: NM_000015702.3. 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			3	99	1	103
missense	1	3	71	7	2	84
nonsense	12	8	1			21
start loss						0
frameshift	20	10	2			32
splice donor/acceptor (+/-2bp)		14				14
Total	33	35	77	106	3

Highest pathogenic variant AF is 0.0000377987

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MMADHC	protein_coding	protein_coding	ENST00000428879	7	18183

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0000207	0.908	125716	0	24	125740	0.0000954

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.413	168	154	1.09	0.00000713	1934
Missense in Polyphen		50	49.785	1.0043		600
Synonymous	-0.246	54	51.7	1.04	0.00000237	565
Loss of Function	1.58	10	17.1	0.586	0.00000102	187

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000119	0.000119
Ashkenazi Jewish	0.00	0.00
East Asian	0.000273	0.000272
Finnish	0.00	0.00
European (Non-Finnish)	0.000123	0.000123
Middle Eastern	0.000273	0.000272
South Asian	0.0000328	0.0000327
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Involved in cobalamin metabolism (PubMed:18385497, PubMed:23415655, PubMed:24722857, PubMed:26364851). Plays a role in regulating the biosynthesis of two coenzymes, methylcobalamin and adenosylcobalamin (PubMed:18385497, PubMed:24722857). Plays a role in regulating the proportion of methylcobalamin and adenosylcobalamin (PubMed:23415655, PubMed:24722857). Promotes oxidation of cob(II)alamin bound to MMACHC (PubMed:26364851). {ECO:0000269|PubMed:18385497, ECO:0000269|PubMed:23415655, ECO:0000269|PubMed:24722857, ECO:0000269|PubMed:26364851}.
• Pathway: Cobalamin (Cbl, vitamin B12) transport and metabolism;Metabolism;Metabolism of water-soluble vitamins and cofactors;Metabolism of vitamins and cofactors (Consensus)

Recessive Scores

• pRec: 0.133

Intolerance Scores

• loftool: 0.313
• rvis_EVS: 0.48
• rvis_percentile_EVS: 79.25

Haploinsufficiency Scores

• pHI: 0.174
• hipred: N
• hipred_score: 0.333
• ghis: 0.472

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.531

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Mmadhc

Gene ontology

• Biological process: coenzyme biosynthetic process;cobalamin metabolic process
• Cellular component: cytoplasm;mitochondrion;cytosol
• Molecular function: protein binding