AGPAT2

protein-coding

1-acylglycerol-3-phosphate O-acyltransferase 2, the group of 1-acylglycerol-3-phosphate O-acyltransferases

Gene summary

This gene encodes a member of the 1-acylglycerol-3-phosphate O-acyltransferase family. The protein is located within the endoplasmic reticulum membrane and converts lysophosphatidic acid to phosphatidic acid, the second step in de novo phospholipid biosynthesis. Mutations in this gene have been associated with congenital generalized lipodystrophy (CGL), or Berardinelli-Seip syndrome, a disease characterized by a near absence of adipose tissue and severe insulin resistance. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

Previous symbols:

BSCL

MANE transcript

NM_006412.4

Inheritance

ClinVar variants

P:37U:118B:61

Top phenotype

Lipodystrophy, congenital generalized, type 1

gnomAD constraint

pLI —, LoF o/e 0.94

Max pathogenic AF

—

Genomic locus

chr9:136,673,143-136,687,457

External References & Databases

Ensembl (ENSG00000169692)

Transcript & Mutation Effects

hg38 • Region Span ~14.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neonatal diabetes mellitusLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0016391

Submitter: Genomics England PanelApp

lipodystrophyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0006573

Submitter: ClinGen

Human pathogenic *AGPAT2* variants were first reported in 2002 in association with autosomal recessive congenital generalized lipodystrophy (Agarwal et al, PMID:11967537). We have curated the inheritance pattern for *AGPAT2* - related lipodystrophy as autosomal recessive because a recessive mode of inheritance has been consistently reported since 2002 (Agarwal et al, PMIDs:12765973; 11967537; Gorin et al, PMID:32412105). Homozygous or compound heterozygous variants, including nonsense, splice site, frameshift variants and small deletions have been reported. Typical autosomal recessive cases due to homozygous or compound heterozygous variants presented with hypertriglyceridemia, hepatic steatosis, hyperinsulinemia, pancreatitis and diabetes mellitus features even in early childhood and adolescence (Magre et al, PMID: 12765973; Gorin et al et al, PMID:32412105; Abuzenadah et al, PMID:38231342). At least 50 lipodystrophy-causing *AGPAT2* variants (primarily nonsense or frameshift) have been reported in humans. Evidence supporting the association of this gene with lipodystrophy includes case-level data, segregation data, and experimental data. The aggregated score for case-level and segregation data is 12 points. Variants in this gene were curated for this summary in 12 probands in 8 publications (PMIDs: 38231342,35474974, 32153340, 32412105, 32280377, 23430550, 22902344,12765973), with cases presenting as congenital, generalized lipodystrophy. More evidence is available to support the gene-disease association in the literature, but as the maximum score for genetic evidence (12 points) has been reached; this has not been curated exhaustively. This gene-disease relationship is supported by functional assays (both individual and massively parallel), knockout mouse models, expression studies and functional alterations (PMIDs: 21051554, 38127985, 27408775, 37752957, 38623324). Total points for the experimental evidence are 5. Total points for genetic and experimental evidence together are 17. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no differences in inheritance pattern and phenotypic variability. Therefore, we curated AGPAT2 as associated with autosomal recessive congenital, generalized lipodystrophy (OMIM: 608594) and have been lumped in a single gene curation of lipodystrophy (MONDO: 0006573). In summary, *AGPAT2* is definitively associated with autosomal recessive, congenital generalized lipodystrophy from birth or early infancy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Monogenic Diabetes GCEP on November 13, 2024 (SOP Version 11).

congenital generalized lipodystrophy type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012071

Submitter: Labcorp Genetics (formerly Invitae)

congenital generalized lipodystrophy type 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012071

Submitter: G2P

congenital generalized lipodystrophy type 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012071

Submitter: Natera

congenital generalized lipodystrophy type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012071

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Lipodystrophy, congenital generalized, type 1AR

Manifestation: Cardiovascular; Endocrine; Gastrointestinal; Musculoskeletal

Intervention: Cardiovascular; Endocrine; Gastrointestinal

Rationale: Dietary measures (eg, restriction of fat intake to 20-30% of total dietary energy) and medications (eg, leptin, though availability may be limited) may be beneficial; Surveillance for manifestations, including diabetes and cardiac and hepatic manifestations, may allow early diagnosis and treatment

Refs: 8783769; 11967537; 14602785; 14557463; 15181077; 17671040; 17118991; 19278620; 20301391

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AGPAT2 variants in ClinVar

9 Conditions Cataloged

Congenital generalized lipodystrophy type 1Total: 146

not providedTotal: 116

Inborn genetic diseasesTotal: 53

not specifiedTotal: 40

AGPAT2-related disorderTotal: 14

Monogenic diabetesTotal: 12

Congenital generalized lipodystrophyTotal: 3

Lipodystrophy - childhood onsetTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006412.4. 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			6 clinvar	43 clinvar	1 clinvar	50
missense	2 clinvar	5 clinvar	102 clinvar	16 clinvar	1 clinvar	126
nonsense	5 clinvar	3 clinvar	2 clinvar			10
start loss						0
frameshift	6 clinvar	9 clinvar	3 clinvar			18
splice donor/acceptor (+/-2bp)	3 clinvar	4 clinvar	5 clinvar			12
Total	16	21	118	59	2	216

Highest pathogenic variant AF is 0.00022042615

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 36 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006412.4	RefSeq	NP_006403.2	6	MANE Select
ENST00000371696.7	Ensembl	ENSP00000360761.2	6	MANE Select
NM_001012727.2	RefSeq	NP_001012745.1	5	Standard
ENST00000371694.7	Ensembl	ENSP00000360759.3	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glycerolipid metabolism - Homo sapiens (human)
Glycerophospholipid metabolism - Homo sapiens (human)
Fat digestion and absorption - Homo sapiens (human)
Phospholipase D signaling pathway - Homo sapiens (human)
Adipogenesis

Biological Process

positive regulation of cytokine production
positive regulation of cytokine-mediated signaling pathway
phospholipid metabolic process
phosphatidic acid biosynthetic process
epidermis development

Molecular Function

1-acylglycerol-3-phosphate O-acyltransferase activity

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
plasma membrane
integral component of membrane
specific granule membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000371696
Coding exons: 6
Length: 14281
Individuals with no LoFs: 125585
Homozygous LoFs: 0
Heterozygous LoFs: 25
Defined: 125610
p: 0.0000995

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.722	199	172	1.15	0.0000118	1762
Missense (PolyPhen)		37	40.555	0.91233		428
Synonymous	-1.51	97	79.8	1.22	0.00000560	588
Loss of Function	0.199	11	11.7	0.937	6.90e-7	115

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00014	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000064	0.000062	rare
South Asian	0.00017	0.00016	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Converts lysophosphatidic acid (LPA) into phosphatidic acid by incorporating an acyl moiety at the sn-2 position of the glycerol backbone. {ECO:0000269|PubMed:15629135, ECO:0000269|PubMed:21873652, ECO:0000269|PubMed:9242711}.;
Disease: DISEASE: Congenital generalized lipodystrophy 1 (CGL1) [MIM:608594]: An autosomal recessive disorder characterized by a near complete absence of adipose tissue, extreme insulin resistance, hypertriglyceridemia, hepatic steatosis and early onset of diabetes. {ECO:0000269|PubMed:11967537, ECO:0000269|PubMed:15629135}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.160

Intolerance Scores

LoFtool: 0.108
RVIS EVS: 0.2
RVIS percentile EVS: 67.3

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.986

Gene Damage Prediction

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