MTHFD1L

protein-coding

methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1 like

Gene summary

The protein encoded by this gene is involved in the synthesis of tetrahydrofolate (THF) in the mitochondrion. THF is important in the de novo synthesis of purines and thymidylate and in the regeneration of methionine from homocysteine. Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jun 2011]

Previous symbols:

FTHFSDC1

MANE transcript

NM_015440.5

Inheritance

—

ClinVar variants

U:168B:5

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.53

Max pathogenic AF

—

Genomic locus

chr6:150,865,679-151,101,887

External References & Databases

Ensembl (ENSG00000120254)

Transcript & Mutation Effects

hg38 • Region Span ~236.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MTHFD1L variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 155

not providedTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015440.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar		1 clinvar	6
missense			155 clinvar	4 clinvar		159
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			8 clinvar			8
Total	0	0	168	4	1	173

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 65 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015440.5	RefSeq	NP_056255.2	27	MANE Select
ENST00000367321.8	Ensembl	ENSP00000356290.3	27	MANE Select
NM_001242767.2	RefSeq	NP_001229696.1	27	Standard
NM_001242768.2	RefSeq	NP_001229697.1	27	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

One carbon pool by folate - Homo sapiens (human)
Folate malabsorption, hereditary
Methylenetetrahydrofolate Reductase Deficiency (MTHFRD)
Methotrexate Action Pathway
Folate Metabolism

Biological Process

neural tube closure
folic acid-containing compound metabolic process
purine nucleobase biosynthetic process
10-formyltetrahydrofolate biosynthetic process
formate metabolic process

Molecular Function

formate-tetrahydrofolate ligase activity
methylenetetrahydrofolate dehydrogenase (NADP+) activity
ATP binding
protein homodimerization activity

Cellular Component

cytoplasm
mitochondrion
mitochondrial matrix
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000367321
Coding exons: 27
Length: 236339
Individuals with no LoFs: 125666
Homozygous LoFs: 0
Heterozygous LoFs: 82
Defined: 125748
p: 0.000326

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.992	459	523	0.878	0.0000294	6309
Missense (PolyPhen)		162	217.99	0.74316		2388
Synonymous	-0.226	208	204	1.02	0.0000128	1982
Loss of Function	3.17	28	52.9	0.529	0.00000285	618

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00049	0.00049	rare
Finnish	0.00018	0.00018	rare
European (Non-Finnish)	0.00042	0.00042	rare
South Asian	0.00043	0.00042	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May provide the missing metabolic reaction required to link the mitochondria and the cytoplasm in the mammalian model of one-carbon folate metabolism in embryonic an transformed cells complementing thus the enzymatic activities of MTHFD2. {ECO:0000250, ECO:0000269|PubMed:16171773}.;

Recessive Scores

pRec: 0.261

Intolerance Scores

LoFtool: 0.815
RVIS EVS: -0.35
RVIS percentile EVS: 29.54

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.900

Gene Damage Prediction

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