TENM4

Chr 11AD

teneurin transmembrane protein 4

Also known as: Doc4, ETM5, ODZ4, TEN4, TNM4, Ten-M4, ten-4

NCBI Gene: 26011ENSG00000149256UniProt: Q6N022OMIM: 610084

The protein encoded by TENM4 regulates neural development by establishing proper neuronal connectivity and promoting oligodendrocyte differentiation and myelination of small-diameter axons in the central nervous system. Mutations cause hereditary essential tremor-5, inherited in an autosomal dominant pattern. The gene is highly constrained against loss-of-function variants, indicating intolerance to protein-disrupting mutations.

OMIMResearchSummary from RefSeq, OMIM, UniProt
MultiplemechanismADLOEUF 0.171 OMIM phenotype
Clinical Summary— TENM4
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
1 unique Pathogenic / Likely Pathogenic· 390 VUS of 500 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.17LOEUF
pLI 1.000
Z-score 8.51
OE 0.10 (0.07–0.17)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
2.73Z-score
OE missense 0.81 (0.77–0.85)
1341 obs / 1653.7 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.10 (0.07–0.17)
0≤0.351.4
Missense OE0.81 (0.77–0.85)
0≤0.61.4
Synonymous OE0.88
0≤1.21.6
LoF obs/exp: 11 / 105.2Missense obs/exp: 1341 / 1653.7Syn Z: 2.38
DN
0.3694th %ile
GOF
0.3986th %ile
LOF
0.70top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.17
DN1 literature citation

Literature Evidence

DNTransfection of the mutation into an oligodendrocyte cell line showed that the mutant protein clustered at the membrane, whereas the wildtype protein localized homogeneously at the membrane. Injection of the mutation into zebrafish embryos resulted in a defect in axonal guidance similar to that obsePMID:26188006

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

500 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1
VUS390
Likely Benign54
Benign21
Conflicting1
1
Pathogenic
390
VUS
54
Likely Benign
21
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
1
0
1
Likely Pathogenic
0
0
0
0
0
VUS
2
385
0
3
390
Likely Benign
0
8
7
39
54
Benign
0
8
0
13
21
Conflicting
—1
Total2401855467

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

View in ClinVar →

Protein Context — Lollipop Plot

TENM4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 4 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients