MBOAT7

protein-coding

membrane bound O-acyltransferase domain containing 7, the group of Membrane bound O-acyltransferase family

Gene summary

This gene encodes a member of the membrane-bound O-acyltransferases family of integral membrane proteins that have acyltransferase activity. The encoded protein is a lysophosphatidylinositol acyltransferase that has specificity for arachidonoyl-CoA as an acyl donor. This protein is involved in the reacylation of phospholipids as part of the phospholipid remodeling pathway known as the Land cycle. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2009]

Previous symbols:

LENG4

MANE transcript

NM_024298.5

Inheritance

ClinVar variants

P:31U:153B:47

Top phenotype

Intellectual developmental disorder, autosomal recessive 57

gnomAD constraint

pLI —, LoF o/e 0.28

Max pathogenic AF

—

Genomic locus

chr19:54,173,412-54,189,882

External References & Databases

Ensembl (ENSG00000125505)

Transcript & Mutation Effects

hg38 • Region Span ~16.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual disability, autosomal recessive 57STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014962

Submitter: PanelApp Australia

intellectual disability, autosomal recessive 57STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014962

Submitter: Labcorp Genetics (formerly Invitae)

intellectual disability, autosomal recessive 57STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014962

Submitter: G2P

intellectual disability, autosomal recessive 57STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014962

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.

intellectual disability, autosomal recessive 57MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014962

Submitter: Ambry Genetics

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: ClinGen

*MBOAT7* encodes an enzyme that regulates arachidonic acid incorporation in lysophosphatidylinositol. *MBOAT7* was first reported in relation to autosomal recessive complex neurodevelopmental disorder in 2016 (Johansen et al., PMID: 27616480). Probands with variants in *MBOAT7* frequently have the phenotypic features of moderate to severe developmental delay, absent speech, infant-onset epilepsy, truncal hypotonia and autistic features. Eight variants (nonsense, frameshift and splice-site) that have been reported in ten probands in four publications (PMIDs: 27616480, 32645526, 31282596, 3335874) are included in this curation. All variants described were homozygous, and one variant, c.758_778del, was reported in three unrelated families. More evidence is available in the literature (PMID: 30701556), but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported as loss of function (PMID: 27616480). This gene-disease relationship is also supported by a knock-out Mboat7 mouse model (PMID: 23097495). This model showed complete ablation of Mboat7 enzyme activity, an absence of the protein in brain tissue, and displayed atrophy of the cerebral cortex, disordered cortical lamination, and delayed neuron migration. Additionally, expression of two disease-related variants in HepG2 cells (p.(Tyr354*) and p.(Leu379Trpfs*9)) showed absent Mboat7 protein on western blot (PMID: 32645526). In summary, there is definitive evidence supporting the relationship between *MBOAT7* and autosomal recessive complex neurodevelopmental disorder. 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 Intellectual Disability and Autism GCEP on the meeting date November 21, 2023 (SOP Version 10).

autosomal recessive non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019502

Submitter: Orphanet

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal recessive 57AR

Manifestation: 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: 27616480

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MBOAT7 variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 115

not providedTotal: 73

Intellectual disability, autosomal recessive 57Total: 43

not specifiedTotal: 37

MBOAT7-related disorderTotal: 16

MBOAT7-related disordersTotal: 5

Intellectual disabilityTotal: 3

Neurodevelopmental abnormalityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024298.5. 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			2 clinvar	42 clinvar		44
missense		1 clinvar	136 clinvar	5 clinvar		142
nonsense	1 clinvar	6 clinvar	2 clinvar			9
start loss			2 clinvar			2
frameshift	7 clinvar	12 clinvar	5 clinvar			24
splice donor/acceptor (+/-2bp)	2 clinvar	2 clinvar	6 clinvar			10
Total	10	21	153	47	0	231

Highest pathogenic variant AF is 0.000052546413

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024298.5	RefSeq	NP_077274.3	7	MANE Select
ENST00000245615.6	Ensembl	ENSP00000245615.1	7	MANE Select
NM_001146056.3	RefSeq	NP_001139528.1	5	Standard
NM_001146082.3	RefSeq	NP_001139554.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glycerophospholipid metabolism - Homo sapiens (human)
Acyl chain remodelling of PI
Metabolism of lipids
Metabolism
CDP-diacylglycerol biosynthesis

Biological Process

phospholipid biosynthetic process
ventricular system development
layer formation in cerebral cortex
phosphatidylinositol acyl-chain remodeling

Molecular Function

1-acylglycerol-3-phosphate O-acyltransferase activity
protein binding
2-acylglycerol-3-phosphate O-acyltransferase activity
lysophospholipid acyltransferase activity

Cellular Component

endoplasmic reticulum membrane
membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000245615
Coding exons: 7
Length: 16627
Individuals with no LoFs: 125731
Homozygous LoFs: 0
Heterozygous LoFs: 15
Defined: 125746
p: 0.0000596

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.441	274	295	0.928	0.0000203	2959
Missense (PolyPhen)		74	92.4	0.80087		959
Synonymous	-1.51	156	134	1.17	0.00000949	1020
Loss of Function	2.85	5	18.1	0.276	8.58e-7	199

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.00018	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000051	0.000046	rare
European (Non-Finnish)	0.000048	0.000044	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acyltransferase which contributes to the regulation of free arachidonic acid (AA) in the cell through the remodeling of phospholipids. Mediates the conversion of lysophosphatidylinositol (1-acylglycerophosphatidylinositol or LPI) into phosphatidylinositol (1,2-diacyl-sn-glycero-3-phosphoinositol or PI) (LPIAT activity). Prefers arachidonoyl-CoA as the acyl donor. Lysophospholipid acyltransferases (LPLATs) catalyze the reacylation step of the phospholipid remodeling pathway also known as the Lands cycle. Required for cortical lamination during brain development (By similarity). {ECO:0000250|UniProtKB:Q8CHK3, ECO:0000269|PubMed:18094042, ECO:0000269|PubMed:18772128}.;

Intolerance Scores

LoFtool: 0.690
RVIS EVS: -0.53
RVIS percentile EVS: 20.7

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.283

Gene Damage Prediction

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