FTCD

protein-coding

formimidoyltransferase cyclodeaminase

Gene summary

The protein encoded by this gene is a bifunctional enzyme that channels 1-carbon units from formiminoglutamate, a metabolite of the histidine degradation pathway, to the folate pool. Mutations in this gene are associated with glutamate formiminotransferase deficiency. Alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Dec 2009]

MANE transcript

NM_206965.2

Inheritance

ClinVar variants

P:41U:190B:102

Top phenotype

Glutamate formiminotransferase deficiency

gnomAD constraint

pLI —, LoF o/e 0.87

Max pathogenic AF

—

Genomic locus

chr21:46,136,160-46,155,579

External References & Databases

Ensembl (ENSG00000160282)

Transcript & Mutation Effects

hg38 • Region Span ~19.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

formiminoglutamic aciduriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009240

Submitter: Labcorp Genetics (formerly Invitae)

formiminoglutamic aciduriaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009240

Submitter: Ambry Genetics

formiminoglutamic aciduriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009240

Submitter: PanelApp Australia

formiminoglutamic aciduriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009240

Submitter: G2P

formiminoglutamic aciduriaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009240

Submitter: Orphanet

formiminoglutamic aciduriaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009240

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Clinical Genomic Database (CGD)

Glutamate formiminotransferase deficiencyAR

Manifestation: Biochemical

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Early descriptions included benefits of folic acid treatment, but later descriptions call this into question, and the clinical consequences of the deficiency are unclear

Refs: 5897668; 5956503; 4413489; 235753; 1272625; 12815595; 22108709; 29178637

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FTCD variants in ClinVar

9 Conditions Cataloged

Glutamate formiminotransferase deficiencyTotal: 288

Inborn genetic diseasesTotal: 142

not providedTotal: 62

not specifiedTotal: 25

FTCD-related disorderTotal: 18

Intellectual disabilityTotal: 8

FTCD-AS1-related disorderTotal: 5

Myoepithelial tumorTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_206965.2. 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			2 clinvar	76 clinvar	5 clinvar	83
missense		1 clinvar	185 clinvar	18 clinvar	3 clinvar	207
nonsense	2 clinvar	7 clinvar				9
start loss						0
frameshift	4 clinvar	20 clinvar	2 clinvar			26
splice donor/acceptor (+/-2bp)		7 clinvar	1 clinvar			8
Total	6	35	190	94	8	333

Highest pathogenic variant AF is 0.004933559

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 100 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_206965.2	RefSeq	NP_996848.1	14	MANE Select
ENST00000397746.8	Ensembl	ENSP00000380854.3	14	MANE Select
NM_001320412.2	RefSeq	NP_001307341.1	15	Standard
NM_006657.3	RefSeq	NP_006648.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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

Biological Process

histidine catabolic process
folic acid-containing compound metabolic process
cytoskeleton organization
histidine catabolic process to glutamate and formamide
histidine catabolic process to glutamate and formate

Molecular Function

protein binding
folic acid binding
microtubule binding
formimidoyltransferase activity
glutamate formimidoyltransferase activity

Cellular Component

Golgi membrane
cytoplasm
endoplasmic reticulum
endoplasmic reticulum-Golgi intermediate compartment
Golgi apparatus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000291670
Coding exons: 14
Length: 19306
Individuals with no LoFs: 125547
Homozygous LoFs: 1
Heterozygous LoFs: 182
Defined: 125730
p: 0.000728

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.350	357	339	1.05	0.0000245	3393
Missense (PolyPhen)		139	139.24	0.99824		1322
Synonymous	-1.85	186	156	1.19	0.0000122	1159
Loss of Function	0.616	24	27.5	0.873	0.00000143	295

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0050	0.0049	notable
Latino/Admixed American	0.00052	0.00052	rare
Ashkenazi Jewish	0.0047	0.0043	notable
East Asian	0.00027	0.00027	rare
Finnish	0.00010	0.000092	rare
European (Non-Finnish)	0.00022	0.00021	rare
South Asian	0.00029	0.00029	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Folate-dependent enzyme, that displays both transferase and deaminase activity. Serves to channel one-carbon units from formiminoglutamate to the folate pool.;
Disease: DISEASE: Glutamate formiminotransferase deficiency (FIGLU-URIA) [MIM:229100]: Autosomal recessive disorder. Features of a severe phenotype, include elevated levels of formiminoglutamate (FIGLU) in the urine in response to histidine administration, megaloblastic anemia, and mental retardation. Features of a mild phenotype include high urinary excretion of FIGLU in the absence of histidine administration, mild developmental delay, and no hematological abnormalities. {ECO:0000269|PubMed:12815595}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.365
RVIS EVS: -0.75
RVIS percentile EVS: 13.74

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.806

Gene Damage Prediction

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