TNPO3

Chr 7AD

transportin 3

Also known as: IPO12, LGMD1F, LGMDD2, MTR10A, TRN-SR, TRN-SR2, TRNSR

NCBI Gene: 23534 ENSG00000064419 UniProt: Q9Y5L0 OMIM: 610032

The protein functions as a nuclear importin that transports serine/arginine-rich splicing factors and other target proteins from the cytoplasm into the nucleus. Mutations cause autosomal dominant limb-girdle muscular dystrophy type 2, affecting the skeletal muscle system. The gene shows low constraint against loss-of-function variants (pLI near 0, LOEUF 0.515), which is consistent with the autosomal dominant inheritance pattern observed clinically.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a nuclear import receptor for serine/arginine-rich (SR) proteins such as the splicing factors SFRS1 and SFRS2. The encoded protein has also been shown to be involved in HIV-1 infection, apparently through interaction with the HIV-1 capsid protein. Several protein-coding and non-coding transcript variants have been found for this gene. [provided by RefSeq, Apr 2020]

OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.521 OMIM phenotype

Clinical Summary— TNPO3

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Gene-Disease Validity (ClinGen)

muscular dystrophy, limb-girdle, autosomal dominant · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

9 unique Pathogenic / Likely Pathogenic· 395 VUS of 805 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.52LOEUF

pLI 0.000

Z-score 4.56

OE 0.36 (0.25–0.52)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

3.44Z-score

OE missense 0.58 (0.52–0.63)

300 obs / 521.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.36 (0.25–0.52)

0≤0.351.4

Missense OE?0.58 (0.52–0.63)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 21 / 58.7Missense obs/exp: 300 / 521.1Syn Z: 0.98

This gene — mechanism propensity

0.6065th %ile

GOF

0.6444th %ile

LOF

0.2969th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction 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.

ClinVar Variant Classifications

805 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic6

VUS395

Likely Benign290

Benign50

Conflicting42

Pathogenic

Likely Pathogenic

395

VUS

290

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	1	0	0	3
Likely Pathogenic	6	0	0	0	6
VUS	43	326	18	8	395
Likely Benign	0	6	134	150	290
Benign	0	1	42	7	50
Conflicting	—				42
Total	51	334	194	165	786

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

25 pathogenic / likely-pathogenic (of 30) ClinVar copy-number / structural variants overlap TNPO3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →