TONSL

Chr 8AR

tonsoku like, DNA repair protein

Also known as: IKBR, NFKBIL2, SEMDSP

NCBI Gene: 4796 ENSG00000160949 UniProt: Q96HA7 OMIM: 604546

The protein functions as a component of the MMS22L-TONSL complex that promotes homologous recombination-mediated repair of DNA double-strand breaks during replication and acts as a histone reader that recognizes newly synthesized histones. Mutations cause spondyloepimetaphyseal dysplasia, sponastrime type, a skeletal dysplasia affecting spine and bone development. This condition follows autosomal recessive inheritance.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is thought to be a negative regulator of NF-kappa-B mediated transcription. The encoded protein may bind NF-kappa-B complexes and trap them in the cytoplasm, preventing them from entering the nucleus and interacting with the DNA. Phosphorylation of this protein targets it for degradation by the ubiquitination pathway, which frees the NF-kappa-B complexes to enter the nucleus. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Spondyloepimetaphyseal dysplasia, sponastrime typeMIM #271510

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Spondyloepimetaphyseal dysplasia, sponastrime type; no ClinGen or GenCC tier

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

0.69

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.69LOEUF

pLI 0.000

Z-score 3.54

OE 0.51 (0.38–0.69)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.09Z-score

OE missense 1.01 (0.95–1.07)

822 obs / 814.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.51 (0.38–0.69)

0≤0.351.4

Missense OE?1.01 (0.95–1.07)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 31 / 60.8Missense obs/exp: 822 / 814.5Syn Z: 0.45

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 26

2,002 rare PASS variants

Rare truncating (LoF)

1 in 720

285 rare PASS variants

Rare synonymous (reference)

1 in 34

923 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TONSL. 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 39	1 in 730
South Asian	~43k	1 in 22	1 in 400
Remaining (unassigned)	~30k	1 in 21	1 in 540
European (Finnish)	~27k	1 in 120	1 in 760
Admixed American	~22k	1 in 21	1 in 910
African / African American	~21k	1 in 28	1 in 950
East Asian	~20k	1 in 29	1 in 610
Ashkenazi Jewish	~13k	1 in 150	1 in 2,500
Middle Eastern	~2,884	1 in 20	1 in 480

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 22 of 26 coding exons well covered in gnomAD exomes; exons 1, 2, 11, 26 marginal. Genomes: all 26.? see exons ↓