RTN3

Chr 11

reticulon 3

Also known as: ASYIP, HAP, NSPL2, NSPLII, RTN3-A1

NCBI Gene: 10313 ENSG00000133318 UniProt: O95197

The RTN3 protein regulates membrane trafficking in the early secretory pathway and forms endoplasmic reticulum tubules, while also inhibiting BACE1 activity and amyloid precursor protein processing. Mutations cause autosomal recessive spastic paraplegia with onset typically in childhood or adolescence, characterized by progressive lower limb spasticity and weakness. The gene shows low constraint against loss-of-function variants (pLI 0.00007, LOEUF 0.624), consistent with recessive inheritance requiring biallelic mutations for disease manifestation.

ResearchSummary from RefSeq, UniProt

This gene belongs to the reticulon family of highly conserved genes that are preferentially expressed in neuroendocrine tissues. This family of proteins interact with, and modulate the activity of beta-amyloid converting enzyme 1 (BACE1), and the production of amyloid-beta. An increase in the expression of any reticulon protein substantially reduces the production of amyloid-beta, suggesting that reticulon proteins are negative modulators of BACE1 in cells. Alternatively spliced transcript variants encoding different isoforms have been found for this gene, and pseudogenes of this gene are located on chromosomes 4 and 12. [provided by RefSeq, May 2012]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.62

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.62LOEUF

pLI 0.000

Z-score 3.24

OE 0.39 (0.25–0.62)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.24Z-score

OE missense 1.03 (0.96–1.10)

546 obs / 530.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.39 (0.25–0.62)

0≤0.351.4

Missense OE?1.03 (0.96–1.10)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 13 / 33.1Missense obs/exp: 546 / 530.5Syn Z: -0.09

Background carrier burden — how many people carry a rare variant somewhere in RTN3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 57

1,420 rare PASS variants

Rare truncating (LoF)

1 in 630

186 rare PASS variants

Rare synonymous (reference)

1 in 69

503 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RTN3. 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 78	1 in 780
South Asian	~43k	1 in 43	1 in 390
Remaining (unassigned)	~30k	1 in 38	1 in 980
European (Finnish)	~27k	1 in 190	1 in 3,300
Admixed American	~22k	1 in 51	1 in 890
African / African American	~21k	1 in 41	1 in 730
East Asian	~20k	1 in 43	1 in 660
Ashkenazi Jewish	~13k	1 in 500	1 in 1,200
Middle Eastern	~2,884	1 in 33	≈ 1 in 960

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 9 coding exons well covered in gnomAD exomes and genomes.? see exons ↓