FPGS

protein-coding

folylpolyglutamate synthase

Gene summary

This gene encodes the folylpolyglutamate synthetase enzyme. This enzyme has a central role in establishing and maintaining both cytosolic and mitochondrial folylpolyglutamate concentrations and, therefore, is essential for folate homeostasis and the survival of proliferating cells. This enzyme catalyzes the ATP-dependent addition of glutamate moieties to folate and folate derivatives. Alternative splicing results in transcript variants encoding different isoforms. [provided by RefSeq, Jan 2014]

MANE transcript

NM_004957.6

Inheritance

—

ClinVar variants

U:80B:10

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.48

Max pathogenic AF

—

Genomic locus

chr9:127,794,597-127,814,494

External References & Databases

Ensembl (ENSG00000136877)

Transcript & Mutation Effects

hg38 • Region Span ~19.9 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 FPGS variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 73

not providedTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004957.6. 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				3 clinvar		3
missense			73 clinvar	6 clinvar	1 clinvar	80
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			7 clinvar			7
Total	0	0	80	9	1	90

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 67 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004957.6	RefSeq	NP_004948.4	15	MANE Select
ENST00000373247.7	Ensembl	ENSP00000362344.2	15	MANE Select
NM_001018078.2	RefSeq	NP_001018088.1	14	Standard
NM_001288803.1	RefSeq	NP_001275732.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Fluoropyrimidine Pathway, Pharmacodynamics
Folate biosynthesis - Homo sapiens (human)
Methotrexate Pathway (Cancer Cell), Pharmacodynamics
Folate malabsorption, hereditary
Methylenetetrahydrofolate Reductase Deficiency (MTHFRD)

Biological Process

liver development
nucleobase-containing compound metabolic process
glutamate metabolic process
one-carbon metabolic process
folic acid-containing compound metabolic process

Molecular Function

tetrahydrofolylpolyglutamate synthase activity
ATP binding
metal ion binding

Cellular Component

cytoplasm
mitochondrion
mitochondrial inner membrane
mitochondrial matrix
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000373247
Coding exons: 15
Length: 19731
Individuals with no LoFs: 125718
Homozygous LoFs: 0
Heterozygous LoFs: 30
Defined: 125748
p: 0.000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.89	239	337	0.710	0.0000207	3684
Missense (PolyPhen)		43	90.364	0.47585		989
Synonymous	0.624	141	151	0.935	0.00000948	1247
Loss of Function	2.68	15	31.1	0.482	0.00000164	322

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.000097	0.000092	rare
European (Non-Finnish)	0.00015	0.00015	rare
South Asian	0.000098	0.000098	rare
Other	0.00035	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes conversion of folates to polyglutamate derivatives allowing concentration of folate compounds in the cell and the intracellular retention of these cofactors, which are important substrates for most of the folate-dependent enzymes that are involved in one-carbon transfer reactions involved in purine, pyrimidine and amino acid synthesis. Unsubstituted reduced folates are the preferred substrates. Metabolizes methotrexate (MTX) to polyglutamates. {ECO:0000269|PubMed:8408018, ECO:0000269|PubMed:8408019, ECO:0000269|PubMed:8408021, ECO:0000269|PubMed:8662720}.;

Recessive Scores

pRec: 0.270

Intolerance Scores

LoFtool: 0.742
RVIS EVS: -0.53
RVIS percentile EVS: 20.7

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.865

Gene Damage Prediction

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