DHFR

dihydrofolate reductase

Basic information

Region (hg38): 5:80626225-80654983

Links

ENSG00000228716 ∙ NCBI:1719 ∙ OMIM:126060 ∙ HGNC:2861 ∙ Uniprot:P00374 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• constitutional megaloblastic anemia with severe neurologic disease (Definitive), mode of inheritance: AR
• constitutional megaloblastic anemia with severe neurologic disease (Moderate), mode of inheritance: AR
• constitutional megaloblastic anemia with severe neurologic disease (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Megaloblastic anemia due to dihydrofolate reductase deficiency	AR	Biochemical	The condition manifests with neurologic sequelae and megaloblastic anemia, and medical management (eg, with folinic acid) may help improve clinical parameters	Biochemical; Hematologic; Neurologic	21310276; 21310277

ClinVar

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

• not provided (433 variants)
• Hereditary cancer-predisposing syndrome (289 variants)
• not specified (52 variants)
• Endometrial carcinoma (47 variants)
• Familial adenomatous polyposis 4 (13 variants)
• Constitutional megaloblastic anemia with severe neurologic disease (10 variants)
• MSH3-related condition (6 variants)
• Inborn genetic diseases (6 variants)
• Cavernous sinus meningioma (1 variants)
• Gastrointestinal stromal tumor (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the DHFR 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	21	1	23
missense			30	1		31
nonsense			1			1
start loss						0
frameshift			2			2
inframe indel						0
splice donor/acceptor (+/-2bp)			2			2
splice region			3	7	2	12
non coding	13	19	264	174	15	485
Total	13	19	300	196	16

Highest pathogenic variant AF is 0.0000119

Variants in DHFR

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

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

Position	Type	Phenotype	Significance	ClinVar
5-80629093-A-G			Likely benign (Jul 26, 2018)
5-80629099-C-T			Likely benign (Aug 19, 2022)
5-80629101-C-T			Uncertain significance (Jul 01, 2022)
5-80629105-T-C			Likely benign (Jan 10, 2024)
5-80629138-C-T			Likely benign (Oct 09, 2023)
5-80629139-T-C			Uncertain significance (Jan 07, 2022)
5-80629150-G-A			Likely benign (Apr 05, 2021)
5-80629150-G-C			Likely benign (Jun 16, 2023)
5-80629166-C-A			Uncertain significance (Nov 23, 2021)
5-80629172-GA-G			Benign (Mar 21, 2022)
5-80629173-A-G			Likely benign (Jun 13, 2022)
5-80629179-T-A			Likely benign (Mar 24, 2023)
5-80629183-T-TAA			Likely benign (Jul 12, 2022)
5-80633863-A-C			Likely benign (Nov 01, 2022)
5-80633864-A-G			Likely benign (Apr 29, 2023)
5-80633865-C-T			Likely benign (Mar 09, 2022)
5-80633866-C-T			Likely benign (Nov 13, 2023)
5-80633867-T-G			Likely benign (Dec 04, 2020)
5-80633868-T-C			Likely benign (Nov 07, 2023)
5-80633869-A-G			Likely benign (Oct 23, 2022)
5-80633891-A-G			Likely benign (Nov 20, 2023)
5-80633904-T-A		Constitutional megaloblastic anemia with severe neurologic disease	Pathogenic (Feb 11, 2011)
5-80633914-G-C			Uncertain significance (May 15, 2022)
5-80633921-C-T			Likely benign (Jan 08, 2024)
5-80633922-G-A			Uncertain significance (Aug 19, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
DHFR	protein_coding	protein_coding	ENST00000439211	6	28756

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0343	0.932	125153	0	9	125162	0.0000360

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.01	68	95.9	0.709	0.00000425	1240
Missense in Polyphen		16	27.548	0.5808		352
Synonymous	0.550	29	33.0	0.878	0.00000154	331
Loss of Function	1.83	4	10.4	0.386	5.03e-7	125

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.000164	0.000163
Finnish	0.00	0.00
European (Non-Finnish)	0.0000354	0.0000353
Middle Eastern	0.000164	0.000163
South Asian	0.0000674	0.0000653
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFR2. {ECO:0000269|PubMed:12096917, ECO:0000269|PubMed:21876188}.
• Pathway: Fluoropyrimidine Pathway, Pharmacodynamics;Antimetabolite Pathway - Folate Cycle, Pharmacodynamics;Folate biosynthesis - Homo sapiens (human);One carbon pool by folate - Homo sapiens (human);Methotrexate Pathway (Cancer Cell), Pharmacodynamics;Thiopurine Pathway, Pharmacokinetics/Pharmacodynamics;Sepiapterin reductase deficiency;Segawa syndrome;Folate malabsorption, hereditary;Pterine Biosynthesis;Methylenetetrahydrofolate Reductase Deficiency (MTHFRD);Methotrexate Action Pathway;Folate Metabolism;Dopa-responsive dystonia;Hyperphenylalaniemia due to guanosine triphosphate cyclohydrolase deficiency;Hyperphenylalaninemia due to 6-pyruvoyltetrahydropterin synthase deficiency (ptps);Hyperphenylalaninemia due to dhpr-deficiency;Fluoropyrimidine Activity;Folate Metabolism;Mitotic G1-G1-S phases;One Carbon Metabolism;Retinoblastoma (RB) in Cancer;Trans-sulfuration and one carbon metabolism;Ethanol effects on histone modifications;Nucleotide Metabolism;cell cycle: g1/s check point;Folate metabolism;Metabolism;Metabolism of folate and pterines;Activation of E2F1 target genes at G1/S;G1/S-Specific Transcription;dTMP <i>de novo</i> biosynthesis (mitochondrial);Mitotic G1-G1/S phases;Metabolism of water-soluble vitamins and cofactors;Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation;Metabolism of cofactors;Metabolism of vitamins and cofactors;G1/S Transition;Cell Cycle;Cell Cycle, Mitotic;E2F transcription factor network (Consensus)

Recessive Scores

• pRec: 0.662

Intolerance Scores

• loftool: 0.689
• rvis_EVS: 0.15
• rvis_percentile_EVS: 64.11

Haploinsufficiency Scores

• pHI: 0.591
• hipred: N
• hipred_score: 0.373
• ghis: 0.541

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.984

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Dhfr
• 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); muscle phenotype; immune system phenotype; homeostasis/metabolism phenotype; cellular phenotype; liver/biliary system phenotype; embryo phenotype; 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); 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)

Zebrafish Information Network

• Gene name: dhfr
• Affected structure: somite border
• Phenotype tag: abnormal
• Phenotype quality: degenerate

Gene ontology

• Biological process: regulation of transcription involved in G1/S transition of mitotic cell cycle;tetrahydrobiopterin biosynthetic process;one-carbon metabolic process;negative regulation of translation;axon regeneration;response to methotrexate;dihydrofolate metabolic process;tetrahydrofolate metabolic process;tetrahydrofolate biosynthetic process;folic acid metabolic process;positive regulation of nitric-oxide synthase activity;oxidation-reduction process;regulation of removal of superoxide radicals
• Cellular component: cellular_component;mitochondrion;cytosol
• Molecular function: translation repressor activity, mRNA regulatory element binding;mRNA binding;dihydrofolate reductase activity;folic acid binding;drug binding;folate reductase activity;NADP binding;methotrexate binding;NADPH binding;sequence-specific mRNA binding