FDFT1

protein-coding

farnesyl-diphosphate farnesyltransferase 1

Gene summary

This gene encodes a membrane-associated enzyme located at a branch point in the mevalonate pathway. The encoded protein is the first specific enzyme in cholesterol biosynthesis, catalyzing the dimerization of two molecules of farnesyl diphosphate in a two-step reaction to form squalene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_004462.5

Inheritance

ClinVar variants

P:2U:105B:35

Top phenotype

Squalene synthase deficiency

gnomAD constraint

pLI —, LoF o/e 1.1

Max pathogenic AF

—

Genomic locus

chr8:11,795,573-11,839,395

External References & Databases

Ensembl (ENSG00000079459)

Transcript & Mutation Effects

hg38 • Region Span ~43.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

squalene synthase deficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032566

Submitter: Labcorp Genetics (formerly Invitae)

squalene synthase deficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032566

Submitter: G2P

retinitis pigmentosaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019200

Submitter: G2P

squalene synthase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032566

Submitter: PanelApp Australia

squalene synthase deficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032566

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Squalene synthase deficiencyAR

Manifestation: Biochemical; Cardiovascular; Craniofacial; Gastrointestinal; Musculoskeletal; Neurologic

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

Refs: 29909962

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FDFT1 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 132

FDFT1-related disorderTotal: 37

not providedTotal: 33

Squalene synthase deficiencyTotal: 11

See casesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004462.5. 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			1 clinvar	26 clinvar	2 clinvar	29
missense			102 clinvar	5 clinvar	2 clinvar	109
nonsense		2 clinvar				2
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	2	105	31	4	142

Highest pathogenic variant AF is 0.0000021592396

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 109 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004462.5	RefSeq	NP_004453.3	8	MANE Select
ENST00000220584.9	Ensembl	ENSP00000220584.4	8	MANE Select
NM_001287742.2	RefSeq	NP_001274671.1	8	Standard
NM_001287743.2	RefSeq	NP_001274672.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Steroid biosynthesis - Homo sapiens (human)
Bisphosphonate Pathway, Pharmacodynamics
Statin Pathway, Pharmacodynamics
Simvastatin Action Pathway
Pravastatin Action Pathway

Biological Process

steroid biosynthetic process
cholesterol biosynthetic process
ergosterol biosynthetic process
isoprenoid biosynthetic process
regulation of lipid metabolic process

Molecular Function

farnesyl-diphosphate farnesyltransferase activity
protein binding
squalene synthase activity

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000220584
Coding exons: 8
Length: 43737
Individuals with no LoFs: 125700
Homozygous LoFs: 0
Heterozygous LoFs: 48
Defined: 125748
p: 0.000191

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-3.88	408	239	1.71	0.0000129	2754
Missense (PolyPhen)		105	78.436	1.3387		962
Synonymous	-7.30	172	86.0	2.00	0.00000452	768
Loss of Function	-0.394	21	19.1	1.10	8.96e-7	233

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.000095	0.000087	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00033	0.00033	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00025	0.00025	rare
South Asian	0.00010	0.000098	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Recessive Scores

pRec: 0.267

Intolerance Scores

LoFtool: 0.320
RVIS EVS: -1.13
RVIS percentile EVS: 6.48

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.999

Gene Damage Prediction

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