DNAAF8

Chr 16

dynein axonemal assembly factor 8

Also known as: C16orf71, Daap1

NCBI Gene: 146562 ENSG00000166246 UniProt: Q8IYS4

This protein enables dynein complex binding and is required for deployment of outer dynein arms to the axoneme in ciliated cells. Mutations cause primary ciliary dyskinesia, a disorder affecting respiratory function, fertility, and organ positioning that typically presents in infancy or early childhood. Primary ciliary dyskinesia follows autosomal recessive inheritance.

ResearchSummary from RefSeq, UniProt

MultiplemechanismLOEUF 1.52

Clinical Summary— DNAAF8

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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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ClinVar Variants

28 unique Pathogenic / Likely Pathogenic· 18 VUS of 57 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

1.52LOEUF

pLI 0.000

Z-score -0.50

OE 1.11 (0.82–1.52)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint

-1.41Z-score

OE missense 1.23 (1.13–1.34)

368 obs / 299.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios

LoF OE1.11 (0.82–1.52)

0≤0.351.4

Missense OE1.23 (1.13–1.34)

0≤0.61.4

Synonymous OE1.11

0≤1.21.6

LoF obs/exp: 28 / 25.3Missense obs/exp: 368 / 299.2Syn Z: -1.02

0.6260th %ile

GOF

0.6443th %ile

LOF

0.4037th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

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.