TINF2

Chr 14AD

TERF1 interacting nuclear factor 2

Also known as: DKCA3, DKCA5, TIN2

NCBI Gene: 26277 ENSG00000092330 UniProt: Q9BSI4 OMIM: 604319

The protein is a critical component of the shelterin complex that protects telomeres from being recognized as DNA breaks and regulates telomere length. Mutations cause dyskeratosis congenita and Revesz syndrome, inherited bone marrow failure syndromes that affect multiple organ systems including skin, nails, and hematopoietic system. The gene follows autosomal dominant inheritance and is highly constrained against loss-of-function variants.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes one of the proteins of the shelterin, or telosome, complex which protects telomeres by allowing the cell to distinguish between telomeres and regions of DNA damage. The protein encoded by this gene is a critical part of shelterin; it interacts with the three DNA-binding proteins of the shelterin complex, and it is important for assembly of the complex. Mutations in this gene cause dyskeratosis congenita (DKC), an inherited bone marrow failure syndrome. [provided by RefSeq, Mar 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Dyskeratosis congenita, autosomal dominant 3MIM #613990

Revesz syndromeMIM #268130

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · dyskeratosis congenita, autosomal dominant 3 · AD · ClinGen 2025

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.67

LOEUF

LOF*

Mechanism· G2P

📖

GeneReview available — TINF2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.67LOEUF

pLI 0.001

Z-score 2.76

OE 0.38 (0.23–0.67)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.73Z-score

OE missense 0.87 (0.77–0.97)

203 obs / 234.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.38 (0.23–0.67)

0≤0.351.4

Missense OE?0.87 (0.77–0.97)

0≤0.61.4

Synonymous OE?1.22

0≤1.21.6

LoF obs/exp: 9 / 23.4Missense obs/exp: 203 / 234.2Syn Z: -1.71

Background carrier burden — how many people carry a rare variant somewhere in TINF2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 99

553 rare PASS variants

Rare truncating (LoF)

1 in 1,700

85 rare PASS variants

Rare synonymous (reference)

1 in 300

243 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TINF2. 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 190	1 in 1,600
South Asian	~43k	1 in 120	1 in 6,200
Remaining (unassigned)	~30k	1 in 130	1 in 1,800
European (Finnish)	~27k	1 in 450	1 in 700
Admixed American	~22k	1 in 140	1 in 2,800
African / African American	~21k	1 in 140	1 in 2,600
East Asian	~20k	1 in 150	1 in 1,100
Ashkenazi Jewish	~13k	1 in 500	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 320	≈ 1 in 2,900

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): All 9 coding exons well covered in gnomAD exomes and genomes.? see exons ↓