GeneBe

TMPO

protein-coding

thymopoietin, the group of LEM domain containing

Gene summary

Through alternative splicing, this gene encodes several distinct LEM domain containing protein isoforms. LEM domain proteins include inner nuclear membrane and intranuclear proteins, and are involved in a variety of cellular functions including gene expression, chromatin organization, and replication and cell cycle control. The encoded alpha isoform is broadly diffuse in the nucleus and contains a lamin binding domain, while the beta and gamma isoforms are localized to the nuclear membrane and contain an HDAC3 interaction domain. The distinct isoforms may compete with each other when acting to chaperone other proteins and regulate transcription. [provided by RefSeq, Aug 2019]

MANE transcript

NM_001032283.3

Inheritance

AD

ClinVar variants

U:164B:102

Top phenotype

Cardiomyopathy, dilated, 1T

gnomAD constraint

pLI —, LoF o/e 0.64

Max pathogenic AF

—

Genomic locus

chr12:98,515,561-98,550,351

External References & Databases

Ensembl (ENSG00000120802)NCBI Gene (7112)OMIM (188380)HGNC:11875GenCCUniProt (P42166, P42167)AlphaFoldClinVar (TMPO)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~34.8 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypertrophic cardiomyopathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005045

Submitter: ClinGen

TMPO was first reported in relation to hypertrophic cardiomyopathy (HCM) in 1 proband in a single 2019 publication (Huang et al 2019, PMID 31277123). The paper reported the same missense variant (Arg690Cys) previously associated with dilated hypertrophic cardiomyopathy (Taylor et al 2005, PMID 16247757), but was later disputed based on high frequency in the gnomAD database, which is consistent with a benign variation. The second variant reported (Vadrot et al. 2023 PMID 36672271) is a frameshift mutation (Gly395Glufs*11) found in 1 male proband. The pathogenicity of this variant was supported by limited functional studies in a cell culture model system that showed reduced protein level and expression, with decrease in cell proliferation and mislocalized truncated protein fragments in the cytoplasm, however the mechanism of disease phenotype remains unclear. The mechanism for disease is unknown. This gene-disease relationship is not supported by other experimental studies. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. The relationship between TMPO and autosomal dominant hypertrophic cardiomyopathy was originally evaluated by the ClinGen Hypertrophic Cardiomyopathy Gene Curation Expert Panel (GCEP) in August 2018 and found to have a no known disease relationship classification. It was re-evaluated in April 2023 by the Hereditary Cardiovascular Disease GCEP. As a result of this recuration, the classification has changed to limited.

dilated cardiomyopathyNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0005021

Submitter: Ambry Genetics

familial isolated dilated cardiomyopathyNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0015470

Submitter: ClinGen

familial hypertrophic cardiomyopathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0024573

Submitter: G2P

familial isolated dilated cardiomyopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015470

Submitter: Orphanet

Clinical Genomic Database (CGD)

Cardiomyopathy, dilated, 1TAD

Manifestation: Cardiovascular

Intervention: Cardiovascular

Rationale: Preventive measures, surveillance (eg, including echocardiography/electrocardiography), and medical management may be helpful to help decrease morbidity

Comments: The onset of symptoms has been described in adults, but surveillance and medical management may be beneficial prior to adulthood

Refs: 16247757Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TMPO variants in ClinVar

17 Conditions Cataloged
not specifiedTotal: 528
Loeys-Dietz syndrome 2Total: 526
not providedTotal: 175
TMPO-related disorderTotal: 27
Primary dilated cardiomyopathyTotal: 6
Dilated cardiomyopathy 1TTotal: 6
CardiomyopathyTotal: 4
Long QT syndromeTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001032283.3. 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.

EffectPLPVUSLBBSum
synonymous
3
clinvar
90
clinvar
1
clinvar
 94
missense
155
clinvar
9
clinvar
2
clinvar
 166
nonsense
1
clinvar
 1
start loss
0
frameshift
3
clinvar
 3
splice donor/acceptor (+/-2bp)
2
clinvar
 2
Total00164993266
Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001032283.3RefSeqNP_001027454.19MANE Select
ENST00000556029.6EnsemblENSP00000450627.19MANE Select
NM_001032284.3RefSeqNP_001027455.16Standard
NM_001307975.2RefSeqNP_001294904.18Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Clearance of Nuclear Envelope Membranes from Chromatin
  • Nuclear Envelope Breakdown
  • Mitotic Prophase
  • Initiation of Nuclear Envelope Reformation
  • Nuclear Envelope Reassembly

Biological Process

  • regulation of transcription, DNA-templated

Molecular Function

  • DNA binding
  • protein binding
  • lamin binding
  • cadherin binding

Cellular Component

  • chromatin
  • nucleus
  • nuclear envelope

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000266732
Coding exons
4
Length
34868
Individuals with no LoFs
125668
Homozygous LoFs
1
Heterozygous LoFs
79
Defined
125748
p
0.000318
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.6083833511.090.00001664463
Missense (PolyPhen)118126.140.93551605
Synonymous-3.171891411.340.000006991444
Loss of Function1.541421.80.6439.98e-7302

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000370.00037rare
Latino/Admixed American0.000690.00069rare
Ashkenazi Jewish0.0000990.000099rare
East Asian0.000380.00038rare
Finnish0.000470.00046rare
European (Non-Finnish)0.000210.00021rare
South Asian0.000290.00026rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: May be involved in the structural organization of the nucleus and in the post-mitotic nuclear assembly. Plays an important role, together with LMNA, in the nuclear anchorage of RB1.;

Recessive Scores

pRec
0.427

Intolerance Scores

LoFtool
0.760
RVIS EVS
1.52
RVIS percentile EVS
95.48

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.881

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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