TTC21B

Chr 2ADAR

tetratricopeptide repeat domain 21B

ENSG00000123607 UniProt: Q7Z4L5 OMIM: 612014

This protein is a component of the intraflagellar transport complex A that is essential for retrograde ciliary transport and negatively modulates sonic hedgehog signaling. Mutations cause nephronophthisis 12 and short-rib thoracic dysplasia 4 with or without polydactyly through both autosomal recessive and autosomal dominant inheritance patterns. The pathogenic mechanism involves dominant-negative effects that disrupt normal ciliary function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs). Essential for retrograde trafficking of IFT-1, IFT-B and GPCRs (PubMed:27932497). Negatively modulates the SHH signal transduction (By similarity)

OMIM ResearchGenerating clinical summary…

DNmechanismAD/ARLOEUF 0.852 OMIM phenotypes

Clinical Summary— TTC21B

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Gene-Disease Validity (ClinGen)

nephronophthisis 12 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.85LOEUF

pLI 0.000

Z-score 2.64

OE 0.68 (0.54–0.85)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.41Z-score

OE missense 1.04 (0.98–1.11)

724 obs / 693.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.68 (0.54–0.85)

0≤0.351.4

Missense OE?1.04 (0.98–1.11)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 53 / 78.2Missense obs/exp: 724 / 693.7Syn Z: -0.92

This gene — mechanism propensity

0.6842th %ile

GOF

0.5661th %ile

LOF

0.2774th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.