TNPO3

protein-coding

transportin 3, the group of Armadillo like helical domain containing|Importins

Gene summary

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]

Previous symbols:

LGMD1F

MANE transcript

NM_012470.4

Inheritance

ClinVar variants

P:11U:386B:191

Top phenotype

Muscular dystrophy, limb-girdle, autosomal dominant 2

gnomAD constraint

pLI —, LoF o/e 0.36

Max pathogenic AF

—

Genomic locus

chr7:128,954,180-129,055,173

External References & Databases

Ensembl (ENSG00000064419)

Transcript & Mutation Effects

hg38 • Region Span ~101.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal dominant limb-girdle muscular dystrophy type 1FSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012034

Submitter: Orphanet

autosomal dominant limb-girdle muscular dystrophy type 1FMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0012034

Submitter: Ambry Genetics

muscular dystrophy, limb-girdle, autosomal dominantDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015151

Submitter: ClinGen

The TNPO3 gene encodes transportin 3, a nuclear import receptor for serine/arginine-rich (SR) proteins, which are essential precursor-mRNA splicing factors. TNPO3 was first reported in relation to autosomal dominant limb-girdle muscular dystrophy (LGMD) in 2013 by two publications characterizing the same large family (Melia et al., Torella et al., PMID: 23543484, 23667635). TNPO3-related autosomal dominant LGMD is also known as LGMDD2 (MIM #608423). Muscle biopsy tissue typically shows centrally nucleated muscle fibers, rimmed vacuoles, and inclusion bodies (PMID: 11517331). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. The genetic evidence for this curation includes 6 pts of variant-level evidence awarded to six probands heterozygous for four unique frameshift variants, all of which extend the protein by ~15-20 amino acids, including an identical 14 amino acids at the C-terminus (PMID: 23543484, 23667635, 31192305, 31071488, 31217819, 32403337; ClinVar SCV005419095.1; LOVD Individual #00436410, who could not be entered into the GCI). Other type of variants in TNPO3 should be interpreted with caution. Transportin-3 with the C-terminal extension displayed altered subcellular localization when expressed in HeLa cells, recapitulating the staining patterns observed in patient muscle tissue (PMID: 23543484). A seventh individual with a fifth frameshift variant resulting in the same extension has been reported without phenotype information (ClinVar SCV004491986.2). Variants in this gene segregated with the disease in three families, with the first large Italian-Spanish family yielding a maximum LOD score of 7.56 with 32 affected individuals, contributing 3 pts of segregation evidence. This gene-disease relationship is also supported by experimental evidence (3 pts), including the protein's transporter function, altered expression in patient tissue, and Drosophila and cell culture models (PMID: 36789274, 32690349, 23543484, 11517331, 34547132). Although the mechanism of disease is not fully understood, TNPO3 variants have been posited to affect multiple systems, including nuclear transport and myofibrillar networks (PMID: 32690349). In summary, there is Definitive evidence supporting the relationship between TNPO3 and autosomal dominant limb girdle muscular dystrophy. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and upheld over time. This classification was approved by the ClinGen Muscular Dystrophies and Myopathies GCEP on March 11, 2025 (SOP Version 11). This gene-disease pair was originally evaluated by the Muscular Dystrophies and Myopathies GCEP in May 2023. It was re-evaluated in March 2025 and upgraded from Moderate to Definitive with the addition of new case and experimental data.

autosomal dominant limb-girdle muscular dystrophy type 1FSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012034

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant limb-girdle muscular dystrophy type 1FSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012034

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Muscular dystrophy, limb-girdle, autosomal dominant 2AD

Manifestation: Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 11222786; 23543484; 23667635

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TNPO3 variants in ClinVar

7 Conditions Cataloged

Autosomal dominant limb-girdle muscular dystrophy type 1FTotal: 625

not providedTotal: 184

Inborn genetic diseasesTotal: 75

not specifiedTotal: 53

TNPO3-related disorderTotal: 16

Scapular wingingTotal: 1

Muscular dystrophy, limb-girdle, autosomal dominantTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012470.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			8 clinvar	171 clinvar	3 clinvar	182
missense	1 clinvar	3 clinvar	328 clinvar	17 clinvar		349
nonsense	1 clinvar		15 clinvar			16
start loss			1 clinvar			1
frameshift		4 clinvar	20 clinvar			24
splice donor/acceptor (+/-2bp)		2 clinvar	14 clinvar			16
Total	2	9	386	188	3	588

Highest pathogenic variant AF is 0.00001053259

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 76 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_012470.4	RefSeq	NP_036602.1	22	MANE Select
ENST00000265388.10	Ensembl	ENSP00000265388.5	22	MANE Select
NM_001191028.3	RefSeq	NP_001177957.2	21	Standard
NM_001382216.1	RefSeq	NP_001369145.1	22	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tnpo3	Danio rerio	Structure: thymus Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

tnpo3

Danio rerio

Structure: thymus

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

protein import into nucleus

Molecular Function

protein binding
protein transporter activity
signaling receptor activity
identical protein binding

Cellular Component

nucleus
cytoplasm
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000265388
Coding exons: 22
Length: 100251
Individuals with no LoFs: 125704
Homozygous LoFs: 0
Heterozygous LoFs: 44
Defined: 125748
p: 0.000175

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.44	300	521	0.576	0.0000286	6015
Missense (PolyPhen)		58	131.76	0.44021		1481
Synonymous	0.983	173	190	0.909	0.00000979	1826
Loss of Function	4.56	21	58.7	0.358	0.00000355	610

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00022	0.00022	rare
Finnish	0.00018	0.00018	rare
European (Non-Finnish)	0.00019	0.00018	rare
South Asian	0.00020	0.00020	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Seems to function in nuclear protein import as nuclear transport receptor. In vitro, mediates the nuclear import of splicing factor SR proteins RBM4, SFRS1 and SFRS2, by recognizing phosphorylated RS domains. {ECO:0000269|PubMed:10366588, ECO:0000269|PubMed:10713112, ECO:0000269|PubMed:11517331, ECO:0000269|PubMed:12628928}.;

Recessive Scores

pRec: 0.114

Intolerance Scores

LoFtool: 0.301
RVIS EVS: -1.18
RVIS percentile EVS: 5.94

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.867

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium