SPNS1

Chr 16

SPNS lysolipid transporter 1, lysophospholipid

ENSG00000169682 UniProt: Q9H2V7 OMIM: 612583

SPNS1 encodes a lysosomal membrane transporter that mediates the efflux of lysophospholipids from lysosomes to the cytosol, playing a critical role in phospholipid salvage pathways and lysosomal homeostasis. Mutations cause autosomal recessive developmental and epileptic encephalopathy with movement abnormalities, typically presenting in infancy. This gene shows moderate constraint against loss-of-function variants (LOEUF 0.596), and the associated neurological phenotype reflects the essential role of lysosomal phospholipid metabolism in brain development and function.

OMIM ResearchSummary from RefSeq, UniProt

Plays a critical role in the phospholipid salvage pathway from lysosomes to the cytosol (PubMed:36161949, PubMed:37075117). Mediates the rate-limiting, proton-dependent, lysosomal efflux of lysophospholipids, which can then be reacylated by acyltransferases in the endoplasmic reticulum to form phospholipids (PubMed:36161949, PubMed:37075117). Selective for zwitterionic headgroups such as lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE), can also transport lysophosphatidylglycerol (LPG), but not other anionic lysophospholipids, sphingosine, nor sphingomyelin (PubMed:36161949). Transports lysophospholipids with saturated, monounsaturated, and polyunsaturated fatty acids, such as 1-hexadecanoyl-sn-glycero-3-phosphocholine, 1-(9Z-octadecenoyl)-sn-glycero-3-phosphocholine and 1-(4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoyl)-sn-glycero-3-phosphocholine, respectively (PubMed:36161949, PubMed:37075117). Can also transport lysoplasmalogen (LPC with a fatty alcohol) such as 1-(1Z-hexadecenyl)-sn-glycero-3-phosphocholine (PubMed:36161949). Lysosomal LPC could function as intracellular signaling messenger (PubMed:37075117). Essential player in lysosomal homeostasis (PubMed:36161949). Crucial for cell survival under conditions of nutrient limitation (PubMed:37075117). May be involved in necrotic or autophagic cell death (PubMed:12815463)

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.60

Clinical Summary— SPNS1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.60LOEUF

pLI 0.020

Z-score 2.97

OE 0.32 (0.18–0.60)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.06Z-score

OE missense 0.69 (0.62–0.77)

237 obs / 344.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.32 (0.18–0.60)

0≤0.351.4

Missense OE?0.69 (0.62–0.77)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 7 / 22.1Missense obs/exp: 237 / 344.4Syn Z: 0.80

This gene — mechanism propensity

0.7229th %ile

GOF

0.75top 25%

LOF

0.2287th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.