TENM4

Chr 11AD

teneurin transmembrane protein 4

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

NCBI Gene: 26011 ENSG00000149256 UniProt: Q6N022 OMIM: 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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene plays a role in establishing proper neuronal connectivity during development. Defects in this gene have been associated with hereditary essential tremor-5. [provided by RefSeq, Oct 2016]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Essential tremor, hereditary, 5MIM #616736

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Essential tremor, hereditary; no ClinGen or GenCC tier

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

0.17

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

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 OE?0.10 (0.07–0.17)

0≤0.351.4

Missense OE?0.81 (0.77–0.85)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 11 / 105.2Missense obs/exp: 1341 / 1653.7Syn Z: 2.38

Background carrier burden — how many people carry a rare variant somewhere in TENM4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 13

3,417 rare PASS variants

Rare truncating (LoF)

1 in 1,700

161 rare PASS variants

Rare synonymous (reference)

1 in 27

1,523 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TENM4. 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 17	1 in 1,900
South Asian	~43k	1 in 14	1 in 4,100
Remaining (unassigned)	~30k	1 in 12	1 in 3,000
European (Finnish)	~27k	1 in 52	1 in 2,000
Admixed American	~22k	1 in 13	1 in 1,000
African / African American	~21k	1 in 14	1 in 2,600
East Asian	~20k	1 in 14	1 in 1,200
Ashkenazi Jewish	~13k	1 in 57	≈ 1 in 3,200
Middle Eastern	~2,884	1 in 13	≈ 1 in 1,400

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): 29 of 30 coding exons well covered in gnomAD exomes; exon 10 marginal. Genomes: 29 of 30 (exon 15 below).? see exons ↓