IPO5

Chr 13

importin 5

Also known as: IMB3, KPNB3, Pse1, RANBP5, imp5

NCBI Gene: 3843 ENSG00000065150 UniProt: O00410

IPO5 encodes importin-5, a nuclear transport receptor that mediates the import of ribosomal proteins and histones from the cytoplasm into the nucleus through nuclear pore complexes. Mutations cause autosomal dominant intellectual disability with developmental delay, and the gene is highly constrained against loss-of-function variants (pLI=1.0, LOEUF=0.12). The phenotype involves primarily neurodevelopmental features affecting cognitive function.

ResearchSummary from RefSeq, UniProt

Nucleocytoplasmic transport, a signal- and energy-dependent process, takes place through nuclear pore complexes embedded in the nuclear envelope. The import of proteins containing a nuclear localization signal (NLS) requires the NLS import receptor, a heterodimer of importin alpha and beta subunits also known as karyopherins. Importin alpha binds the NLS-containing cargo in the cytoplasm and importin beta docks the complex at the cytoplasmic side of the nuclear pore complex. In the presence of nucleoside triphosphates and the small GTP binding protein Ran, the complex moves into the nuclear pore complex and the importin subunits dissociate. Importin alpha enters the nucleoplasm with its passenger protein and importin beta remains at the pore. Interactions between importin beta and the FG repeats of nucleoporins are essential in translocation through the pore complex. The protein encoded by this gene is a member of the importin beta family. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.12

LOEUF· LoF intol.

LOF

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

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.12LOEUF

pLI 1.000

Z-score 7.02

OE 0.05 (0.02–0.12)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

3.36Z-score

OE missense 0.62 (0.56–0.67)

371 obs / 602.8 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.05 (0.02–0.12)

0≤0.351.4

Missense OE?0.62 (0.56–0.67)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 3 / 63.3Missense obs/exp: 371 / 602.8Syn Z: -0.68

Background carrier burden — how many people carry a rare variant somewhere in IPO5?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 63

1,171 rare PASS variants

Rare truncating (LoF)

1 in 910

64 rare PASS variants

Rare synonymous (reference)

1 in 75

543 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for IPO5. 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 63	1 in 850
South Asian	~43k	1 in 62	1 in 4,300
Remaining (unassigned)	~30k	1 in 62	1 in 720
European (Finnish)	~27k	1 in 120	1 in 1,900
Admixed American	~22k	1 in 78	1 in 780
African / African American	~21k	1 in 61	1 in 3,400
East Asian	~20k	1 in 83	1 in 2,800
Ashkenazi Jewish	~13k	1 in 200	≈ 1 in 3,700
Middle Eastern	~2,884	1 in 85	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): 14 of 26 coding exons well covered in gnomAD exomes; exons 4, 5, 7, 8, 9 and 7 more marginal. Genomes: 25 of 26 (exon 17 below).? see exons ↓