MTHFD1

methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1, the group of Minor histocompatibility antigens

Basic information

Region (hg38): 14:64388030-64463457

Previous symbols: [ "MTHFC", "MTHFD" ]

Links

ENSG00000100714 ∙ NCBI:4522 ∙ OMIM:172460 ∙ HGNC:7432 ∙ Uniprot:P11586 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia	AR	Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Biochemical	Individuals have been described as presenting with severe and recurrent infections, as well as other sequelae, such as renal disease, and medical management (with folate and hydroxycobalamin) has been described as beneficial; In addition to folate and hydroxycobalamin treatment, antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; Related to hearing deificits, early recognition and treatment of hearing impairment may improve outcomes, including speech and language development	Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Biochemical; Hematologic; Neurologic; Renal	23296427; 25633902; 27707659

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MTHFD1 gene.

• not provided (381 variants)
• Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia (14 variants)
• Inborn genetic diseases (13 variants)
• not specified (6 variants)
• Severe combined immunodeficiency disease (6 variants)
• Neural tube defects, folate-sensitive;Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia (3 variants)
• MTHFD1-related condition (1 variants)
• Neural tube defects, folate-sensitive, susceptibility to (1 variants)
• See cases (1 variants)
• Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia;Neural tube defects, folate-sensitive (1 variants)
• Spina bifida, folate-sensitive, susceptibility to (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MTHFD1 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	88	4	93
missense		3	170	5	4	182
nonsense	6	4				10
start loss						0
frameshift	2	1				3
inframe indel						0
splice donor/acceptor (+/-2bp)		6				6
splice region			15	17	2	34
non coding			6	55	14	75
Total	8	14	177	148	22

Highest pathogenic variant AF is 0.0000131

Variants in MTHFD1

This is a list of pathogenic ClinVar variants found in the MTHFD1 region.

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

Position	Type	Phenotype	Significance	ClinVar
14-64388445-C-T			Benign (Dec 09, 2023)
14-64388451-C-A			Uncertain significance (Nov 03, 2021)
14-64388456-A-G			Uncertain significance (Feb 25, 2022)
14-64388457-G-A			Likely benign (Mar 20, 2023)
14-64388481-CATT-C			Likely benign (Aug 08, 2023)
14-64388482-ATTG-A			Likely benign (Nov 23, 2022)
14-64400804-C-T		MTHFD1-related disorder	Likely benign (Jan 31, 2024)
14-64400805-G-A			Likely benign (Oct 15, 2023)
14-64400819-A-G			Uncertain significance (Jul 11, 2021)
14-64400855-C-T			Uncertain significance (May 13, 2021)
14-64400860-C-T		Neural tube defects, folate-sensitive;Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia	Uncertain significance (Mar 30, 2021)
14-64400861-G-A		Inborn genetic diseases	Uncertain significance (Nov 03, 2023)
14-64400871-A-G			Uncertain significance (Oct 19, 2022)
14-64400874-A-G			Likely benign (Feb 25, 2023)
14-64400885-G-A			Likely benign (Sep 21, 2022)
14-64400890-T-C			Likely benign (Jul 09, 2023)
14-64411072-A-G			Likely benign (Jul 19, 2023)
14-64411078-T-C			Likely benign (Apr 09, 2023)
14-64411081-T-C			Likely benign (May 11, 2022)
14-64411098-C-T			Likely benign (Oct 13, 2023)
14-64411109-C-T		Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia • Severe combined immunodeficiency disease	Pathogenic/Likely pathogenic (Jan 01, 2024)
14-64411114-CTT-C			Pathogenic (Nov 14, 2023)
14-64411115-T-C		Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia	Likely pathogenic (Oct 15, 2018)
14-64411124-A-G		Inborn genetic diseases	Uncertain significance (Aug 12, 2021)
14-64411151-T-TA			Likely benign (Mar 14, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MTHFD1	protein_coding	protein_coding	ENST00000216605	27	71974

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00446	0.996	125695	0	53	125748	0.000211

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.68	405	512	0.791	0.0000293	6110
Missense in Polyphen		128	205.23	0.62368		2472
Synonymous	-0.172	197	194	1.02	0.0000123	1871
Loss of Function	4.62	14	48.8	0.287	0.00000249	601

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000365	0.000366
Ashkenazi Jewish	0.000596	0.000595
East Asian	0.000272	0.000272
Finnish	0.000370	0.000370
European (Non-Finnish)	0.000211	0.000211
Middle Eastern	0.000272	0.000272
South Asian	0.0000653	0.0000653
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Disease: DISEASE: Neural tube defects, folate-sensitive (NTDFS) [MIM:601634]: The most common NTDs are open spina bifida (myelomeningocele) and anencephaly. {ECO:0000269|PubMed:12384833, ECO:0000269|PubMed:16552426, ECO:0000269|PubMed:9611072}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. {ECO:0000269|PubMed:17000706}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry.; DISEASE: Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia (CIMAH) [MIM:617780]: An autosomal recessive disorder due to an inborn error of folate metabolism. Variable clinical manifestations include hemolytic uremic syndrome, macrocytosis, epilepsy, hearing loss, retinopathy, mild mental retardation, and lymphopenia. {ECO:0000269|PubMed:21813566, ECO:0000269|PubMed:25633902, ECO:0000269|PubMed:27707659}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Antimetabolite Pathway - Folate Cycle, Pharmacodynamics;One carbon pool by folate - Homo sapiens (human);Methotrexate Pathway (Cancer Cell), Pharmacodynamics;Thiopurine Pathway, Pharmacokinetics/Pharmacodynamics;Folate malabsorption, hereditary;Methylenetetrahydrofolate Reductase Deficiency (MTHFRD);Methotrexate Action Pathway;Folate Metabolism;Folate Metabolism;One Carbon Metabolism;Trans-sulfuration and one carbon metabolism;folate polyglutamylation;Folate metabolism;Metabolism;folate transformations I;Metabolism of folate and pterines;histidine degradation;Metabolism of water-soluble vitamins and cofactors;Metabolism of vitamins and cofactors;Vitamin B9 (folate) metabolism;tetrahydrofolate salvage from 5,10-methenyltetrahydrofolate (Consensus)

Recessive Scores

• pRec: 0.210

Intolerance Scores

• loftool: 0.790
• rvis_EVS: 0.38
• rvis_percentile_EVS: 75.63

Haploinsufficiency Scores

• pHI: 0.780
• hipred: Y
• hipred_score: 0.793
• ghis: 0.517

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.553

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Mthfd1
• Phenotype: immune system phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); limbs/digits/tail 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); hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; cellular phenotype; homeostasis/metabolism phenotype; growth/size/body region phenotype

Gene ontology

• Biological process: histidine biosynthetic process;neutrophil homeostasis;neural tube closure;purine nucleotide biosynthetic process;methionine metabolic process;one-carbon metabolic process;heart development;serine family amino acid metabolic process;serine family amino acid biosynthetic process;methionine biosynthetic process;purine nucleobase biosynthetic process;10-formyltetrahydrofolate biosynthetic process;transsulfuration;tetrahydrofolate interconversion;folic acid metabolic process;embryonic neurocranium morphogenesis;embryonic viscerocranium morphogenesis;oxidation-reduction process;somite development
• Cellular component: cytoplasm;mitochondrion;cytosol;membrane;extracellular exosome
• Molecular function: formate-tetrahydrofolate ligase activity;methenyltetrahydrofolate cyclohydrolase activity;methylenetetrahydrofolate dehydrogenase [NAD(P)+] activity;methylenetetrahydrofolate dehydrogenase (NAD+) activity;methylenetetrahydrofolate dehydrogenase (NADP+) activity;protein binding;ATP binding