GNPAT

protein-coding

glyceronephosphate O-acyltransferase

Gene summary

This gene encodes an enzyme located in the peroxisomal membrane which is essential to the synthesis of ether phospholipids. Mutations in this gene are associated with rhizomelic chondrodysplasia punctata. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

MANE transcript

NM_014236.4

Inheritance

ClinVar variants

P:67U:158B:163

Top phenotype

Rhizomelic chondrodysplasia punctata, type 2

gnomAD constraint

pLI —, LoF o/e 0.23

Max pathogenic AF

—

Genomic locus

chr1:231,241,207-231,277,973

External References & Databases

Ensembl (ENSG00000116906)

Transcript & Mutation Effects

hg38 • Region Span ~36.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

rhizomelic chondrodysplasia punctata type 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009112

Submitter: G2P

rhizomelic chondrodysplasia punctata type 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009112

Submitter: Labcorp Genetics (formerly Invitae)

rhizomelic chondrodysplasia punctata, type 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100273

Submitter: ClinGen

The relationship between *GNPAT* and glyceronephosphate O-acyltransferase deficiency (rhizomelic chondrodysplasia punctata type 2 [RCDP2] included), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of July 16, 2019. *GNPAT* encodes glyceronephosphate O-acyltransferase (also known as dihydroxyacetone phosphate acyltransferase; DHAPAT, DAPAT), a peroxisomal enzyme involved in the synthesis of plasmalogens. Deficiency of plasmalogens is a feature of RCDP. Variants in *GNPAT* causing glyceronephosphate O-acyltransferase deficiency were first reported in 1998 (Ofman et al, PMID 9536089). Data from 13 patients with 12 unique variants (missense, nonsense, frameshift, splicing) from 4 publications were curated (Ofman et al, 1998, PMID 9536089; Ofman et al, 2001, PMID 11237722; Thai et al, 2001, PMID 11152660; Nimmo et al, 2010, PMID 20583171; Itzkovitz et al, 2012, PMID 21990100). Additional cases are available in the literature but the maximum score for genetic evidence (12 points) has been reached. The relationship between *GNPAT* and glyceronephosphate O-acyltransferase deficiency is supported by experimental evidence including the biochemical function of GNPAT which is consistent with the biochemical features of the disease (Hajra et al, 1995; PMID 8685243), that other genes with a role in plasmalogen synthesis (AGPS, and PEX7 which encodes the PTS2 receptor necessary for important of AGPS into the peroxisomes) are implicated in causing RCDP (Braverman et al, 1997, PMID 9090381; Itzkovitz et al, 2012, PMID 21990100), and a knock out mouse model which recapitulates the features of the condition (Rodemer et al, 2003, PMID 12874108; Teigler et al, 2009, PMID 19270340). In summary, *GNPAT* is definitively associated with glyceronephosphate O-acyltransferase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Peroxisomal Disorders Gene Curation Expert Panel on February 7, 2020.

rhizomelic chondrodysplasia punctata type 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009112

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Rhizomelic chondrodysplasia punctata, type 2AR

Manifestation: Biochemical; Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

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: 1405476; 8466247; 7530787; 7541833; 9536089; 20583171; 21990100

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GNPAT variants in ClinVar

8 Conditions Cataloged

not providedTotal: 441

Rhizomelic chondrodysplasia punctata type 2Total: 101

Inborn genetic diseasesTotal: 78

not specifiedTotal: 26

GNPAT-related disorderTotal: 6

Rhizomelic chondrodysplasia punctataTotal: 3

Prostate cancerTotal: 1

GNPAT-related disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014236.4. 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			7 clinvar	147 clinvar	2 clinvar	156
missense	1 clinvar	1 clinvar	144 clinvar	12 clinvar	2 clinvar	160
nonsense	6 clinvar	12 clinvar				18
start loss						0
frameshift	16 clinvar	19 clinvar	1 clinvar			36
splice donor/acceptor (+/-2bp)	2 clinvar	10 clinvar	6 clinvar			18
Total	25	42	158	159	4	388

Highest pathogenic variant AF is 0.000010261504

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 85 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014236.4	RefSeq	NP_055051.1	16	MANE Select
ENST00000366647.9	Ensembl	ENSP00000355607.4	16	MANE Select
NM_001316350.2	RefSeq	NP_001303279.1	15	Standard
ENST00000416000.1	Ensembl	ENSP00000411640.1	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glycerophospholipid metabolism - Homo sapiens (human)
Peroxisome - Homo sapiens (human)
Plasmalogen Synthesis
Triacylglyceride Synthesis
Metabolism of lipids

Biological Process

protein targeting to peroxisome
fatty acid metabolic process
phosphatidic acid biosynthetic process
synapse assembly
response to nutrient

Molecular Function

signaling receptor binding
glycerone-phosphate O-acyltransferase activity
palmitoyl-CoA hydrolase activity

Cellular Component

peroxisome
peroxisomal membrane
peroxisomal matrix
cytosol
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000366647
Coding exons: 16
Length: 36767
Individuals with no LoFs: 125727
Homozygous LoFs: 0
Heterozygous LoFs: 21
Defined: 125748
p: 0.0000835

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.674	316	352	0.899	0.0000187	4484
Missense (PolyPhen)		89	111.73	0.79656		1425
Synonymous	-0.0637	125	124	1.01	0.00000634	1282
Loss of Function	4.19	8	34.6	0.231	0.00000181	434

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000097	0.000097	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Rhizomelic chondrodysplasia punctata 2 (RCDP2) [MIM:222765]: A form of rhizomelic chondrodysplasia punctata, a disease characterized by severely disturbed endochondral bone formation, rhizomelic shortening of femur and humerus, vertebral disorders, dwarfism, cataract, cutaneous lesions, facial dysmorphism, and severe mental retardation with spasticity. {ECO:0000269|PubMed:11152660, ECO:0000269|PubMed:21990100, ECO:0000269|PubMed:9536089}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.265

Intolerance Scores

LoFtool: 0.328
RVIS EVS: -0.2
RVIS percentile EVS: 39.11

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.977

Gene Damage Prediction

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