MFSD2A

protein-coding

MFSD2 lysolipid transporter A, lysophospholipid, the group of Solute carrier family 59

Gene summary

The protein encoded by this gene is a transmembrane protein and sodium-dependent lysophosphatidylcholine transporter. The encoded protein is involved in the establishment of the blood-brain barrier and is required for brain growth and function. Defects in this gene are a cause of a progressive microcephaly syndrome. [provided by RefSeq, Mar 2017]

Previous symbols:

MFSD2

MANE transcript

NM_032793.5

Inheritance

ClinVar variants

P:8U:89B:65

Top phenotype

Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain imaging abnormalities

gnomAD constraint

pLI —, LoF o/e 0.31

Max pathogenic AF

—

Genomic locus

chr1:39,955,112-39,969,968

External References & Databases

Ensembl (ENSG00000168389)

Transcript & Mutation Effects

hg38 • Region Span ~14.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

microcephaly 15, primary, autosomal recessiveDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014660

Submitter: G2P

microcephaly 15, primary, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014660

Submitter: PanelApp Australia

microcephaly 15, primary, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014660

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive primary microcephalySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016660

Submitter: Orphanet

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain imaging abnormalitiesAR

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: 26005865; 26005868

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MFSD2A variants in ClinVar

14 Conditions Cataloged

not providedTotal: 152

Inborn genetic diseasesTotal: 53

Microcephaly 15, primary, autosomal recessiveTotal: 17

not specifiedTotal: 13

MFSD2A-related disorderTotal: 8

MicrocephalyTotal: 2

Functional abnormality of male internal genitaliaTotal: 1

Delayed gross motor developmentTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032793.5. 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	56 clinvar	2 clinvar	60
missense	2 clinvar	2 clinvar	81 clinvar	5 clinvar	2 clinvar	92
nonsense	1 clinvar		2 clinvar			3
start loss						0
frameshift	2 clinvar		2 clinvar			4
splice donor/acceptor (+/-2bp)	1 clinvar		2 clinvar			3
Total	6	2	89	61	4	162

Highest pathogenic variant AF is 0.0000095770765

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_032793.5	RefSeq	NP_116182.2	14	MANE Select
ENST00000372811.10	Ensembl	ENSP00000361898.6	14	MANE Select
NM_001136493.3	RefSeq	NP_001129965.1	14	Standard
NM_001287808.2	RefSeq	NP_001274737.1	11	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
mfsd2aa	Danio rerio	Structure: cranial vasculature Quality: porous abnormal

Gene / Model

Organism

Observed Phenotype

mfsd2aa

Danio rerio

Structure: cranial vasculature

Quality: porous

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Metabolism of lipids
Metabolism
Synthesis of PC
Glycerophospholipid biosynthesis
Phospholipid metabolism

Biological Process

phosphatidylcholine biosynthetic process
carbohydrate transport
fatty acid transport
hippocampus development
transcytosis

Molecular Function

transporter activity
phospholipid transporter activity
fatty acid transmembrane transporter activity
symporter activity
lysophospholipid transporter activity

Cellular Component

endoplasmic reticulum membrane
plasma membrane
integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000372809
Coding exons: 14
Length: 14837
Individuals with no LoFs: 125714
Homozygous LoFs: 0
Heterozygous LoFs: 33
Defined: 125747
p: 0.000131

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.04	211	312	0.676	0.0000178	3509
Missense (PolyPhen)		58	138.22	0.41962		1552
Synonymous	1.31	110	129	0.853	0.00000766	1120
Loss of Function	3.47	9	29.2	0.308	0.00000143	326

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0011	0.0011	notable
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00012	0.00011	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0.000065	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Sodium-dependent lysophosphatidylcholine (LPC) symporter, which plays an essential role for blood-brain barrier formation and function (By similarity). Specifically expressed in endothelium of the blood-brain barrier of micro-vessels and transports LPC into the brain (By similarity). Transport of LPC is essential because it constitutes the major mechanism by which docosahexaenoic acid (DHA), an omega-3 fatty acid that is essential for normal brain growth and cognitive function, enters the brain (PubMed:26005868). Transports LPC carrying long-chain fatty acids such LPC oleate and LPC palmitate with a minimum acyl chain length of 14 carbons (By similarity). Does not transport docosahexaenoic acid in unesterified fatty acid (By similarity). Specifically required for blood-brain barrier formation and function, probably by mediating lipid transport (By similarity). Not required for central nervous system vascular morphogenesis (By similarity). Acts as a transporter for tunicamycin, an inhibitor of asparagine-linked glycosylation (PubMed:21677192). In placenta, acts as a receptor for ERVFRD-1/syncytin-2 and is required for trophoblast fusion (PubMed:18988732, PubMed:23177091). {ECO:0000250|UniProtKB:Q9DA75, ECO:0000269|PubMed:18988732, ECO:0000269|PubMed:21677192, ECO:0000269|PubMed:23177091, ECO:0000269|PubMed:26005868}.;
Disease: DISEASE: Microcephaly 15, primary, autosomal recessive (MCPH15) [MIM:616486]: A form of microcephaly, a disease defined as a head circumference more than 3 standard deviations below the age, sex and ethnically matched mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small. {ECO:0000269|PubMed:26005865, ECO:0000269|PubMed:26005868}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0954

Intolerance Scores

LoFtool: 0.131
RVIS EVS: -0.49
RVIS percentile EVS: 22.36

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.231

Gene Damage Prediction

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