SNX15

Chr 11

sorting nexin 15

Also known as: HSAF001435

NCBI Gene: 29907 ENSG00000110025 UniProt: Q9NRS6 OMIM: 605964

SNX15 encodes a sorting nexin protein that regulates intracellular trafficking from the plasma membrane to recycling endosomes and the trans-Golgi network through its phosphoinositide-binding PX domain. Mutations cause autosomal recessive developmental and epileptic encephalopathy with onset in infancy, characterized by severe intellectual disability, seizures, and progressive brain atrophy. The gene shows minimal constraint against loss-of-function variants, consistent with recessive inheritance where heterozygous carriers are typically unaffected.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the sorting nexin family. Members of this family contain a phox (PX) domain, which is a phosphoinositide binding domain, and are involved in intracellular trafficking. Overexpression of this gene results in a decrease in the processing of insulin and hepatocyte growth factor receptors to their mature subunits. This decrease is caused by the mislocalization of furin, the endoprotease responsible for cleavage of insulin and hepatocyte growth factor receptors. This protein is involved in endosomal trafficking from the plasma membrane to recycling endosomes or the trans-Golgi network. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the upstream ADP-ribosylation factor-like 2 (ARL2) gene. [provided by RefSeq, Dec 2010]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.05

LOEUF

GOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.05LOEUF

pLI 0.000

Z-score 1.40

OE 0.64 (0.40–1.05)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.87Z-score

OE missense 0.83 (0.73–0.94)

170 obs / 205.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.64 (0.40–1.05)

0≤0.351.4

Missense OE?0.83 (0.73–0.94)

0≤0.61.4

Synonymous OE?0.83

0≤1.21.6

LoF obs/exp: 11 / 17.3Missense obs/exp: 170 / 205.2Syn Z: 1.20

Background carrier burden — how many people carry a rare variant somewhere in SNX15?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 99

453 rare PASS variants

Rare truncating (LoF)

1 in 1,700

88 rare PASS variants

Rare synonymous (reference)

1 in 280

178 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SNX15. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 120	1 in 1,800
South Asian	~43k	1 in 130	1 in 4,700
Remaining (unassigned)	~30k	1 in 100	1 in 2,000
European (Finnish)	~27k	1 in 470	1 in 500
Admixed American	~22k	1 in 110	1 in 2,400
African / African American	~21k	1 in 90	1 in 2,200
East Asian	~20k	1 in 150	1 in 1,400
Ashkenazi Jewish	~13k	1 in 700	1 in 1,800
Middle Eastern	~2,884	1 in 110	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 8 coding exons well covered in gnomAD exomes and genomes.? see exons ↓