GGPS1

protein-coding

geranylgeranyl diphosphate synthase 1

Gene summary

This gene is a member of the prenyltransferase family and encodes a protein with geranylgeranyl diphosphate (GGPP) synthase activity. The enzyme catalyzes the synthesis of GGPP from farnesyl diphosphate and isopentenyl diphosphate. GGPP is an important molecule responsible for the C20-prenylation of proteins and for the regulation of a nuclear hormone receptor. Alternate transcriptional splice variants, both protein-coding and non-protein-coding, have been found for this gene. [provided by RefSeq, Sep 2010]

MANE transcript

NM_004837.4

Inheritance

ClinVar variants

P:5U:38

Top phenotype

Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome

gnomAD constraint

pLI —, LoF o/e 0.25

Max pathogenic AF

—

Genomic locus

chr1:235,327,350-235,344,532

External References & Databases

Ensembl (ENSG00000152904)

Transcript & Mutation Effects

hg38 • Region Span ~17.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859189

Submitter: PanelApp Australia

muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859189

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndromeAR

Manifestation: Audiologic/Otolaryngologic; Endocrine; Musculoskeletal; Obstetric; Pulmonary

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 32403198

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GGPS1 variants in ClinVar

8 Conditions Cataloged

not specifiedTotal: 22

Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndromeTotal: 9

not providedTotal: 6

Neuromuscular diseaseTotal: 2

Sensorineural hearing loss disorderTotal: 2

MyopathyTotal: 2

Premature ovarian insufficiencyTotal: 1

Myopathy with tubular aggregatesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004837.4. 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	3 clinvar	2 clinvar	32 clinvar			37
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	3	2	38	0	0	43

Highest pathogenic variant AF is 0.000021110905

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 45 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004837.4	RefSeq	NP_004828.1	3	MANE Select
ENST00000282841.9	Ensembl	ENSP00000282841.5	3	MANE Select
NM_001037277.1	RefSeq	NP_001032354.1	3	Standard
NM_001037278.2	RefSeq	NP_001032355.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Terpenoid backbone biosynthesis - Homo sapiens (human)
Simvastatin Action Pathway
Pravastatin Action Pathway
Atorvastatin Action Pathway
Hyper-IgD syndrome

Biological Process

cholesterol biosynthetic process
isoprenoid metabolic process
geranyl diphosphate biosynthetic process
geranylgeranyl diphosphate biosynthetic process
farnesyl diphosphate biosynthetic process

Molecular Function

dimethylallyltranstransferase activity
farnesyltranstransferase activity
geranyltranstransferase activity
protein binding
identical protein binding

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000282841
Coding exons: 3
Length: 17183
Individuals with no LoFs: 125733
Homozygous LoFs: 0
Heterozygous LoFs: 15
Defined: 125748
p: 0.0000596

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.22	113	156	0.726	0.00000777	1980
Missense (PolyPhen)		23	49.328	0.46626		649
Synonymous	-0.935	65	56.1	1.16	0.00000266	555
Loss of Function	2.43	3	12.1	0.248	5.91e-7	158

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000071	0.000070	rare
South Asian	0.000099	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the trans-addition of the three molecules of IPP onto DMAPP to form geranylgeranyl pyrophosphate, an important precursor of carotenoids and geranylated proteins.;

Recessive Scores

pRec: 0.173

Intolerance Scores

LoFtool: 0.618
RVIS EVS: -0.32
RVIS percentile EVS: 31.46

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.939

Gene Damage Prediction

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