TYMSOS

Chr 18Digenic dominant

TYMS opposite strand RNA

Also known as: C18orf56

NCBI Gene: 494514 ENSG00000176912 UniProt: Q8TAI1 OMIM: 188350

TYMSOS encodes a protein involved in telomerase RNA component processing and telomere maintenance. Mutations cause dyskeratosis congenita through a digenic dominant inheritance pattern, requiring variants in this gene plus another gene to manifest disease. This multisystem disorder typically affects the skin, nails, oral mucosa, and bone marrow, with highly variable age of onset.

OMIM ResearchSummary from OMIM

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Dyskeratosis congenita, digenicMIM #620040

Digenic dominant

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Dyskeratosis congenita, digenic; no ClinGen or GenCC tier

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.71

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.71LOEUF

pLI 0.158

Z-score 0.74

OE 0.46 (0.16–1.71)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.94Z-score

OE missense 0.67 (0.53–0.87)

44 obs / 65.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.46 (0.16–1.71)

0≤0.351.4

Missense OE?0.67 (0.53–0.87)

0≤0.61.4

Synonymous OE?0.61

0≤1.21.6

LoF obs/exp: 1 / 2.2Missense obs/exp: 44 / 65.3Syn Z: 1.64

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

none observed

0 rare PASS variants

Rare truncating (LoF)

1 in 32,000

8 rare PASS variants

Rare synonymous (reference)

none observed

0 rare PASS variants

Rare missense and truncating variants are carried at similar rates in TYMSOS; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 5 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	none seen	1 in 58,000
South Asian	~43k	none seen	1 in 2,400
Remaining (unassigned)	~30k	none seen	≈ 1 in 22,000
African / African American	~21k	none seen	≈ 1 in 16,000
East Asian	~20k	none seen	≈ 1 in 18,000

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.