DNAAF1

Chr 16AR

dynein axonemal assembly factor 1

Also known as: CILD13, DAU1, LRRC50, ODA7, swt

NCBI Gene: 123872 ENSG00000154099 UniProt: Q8NEP3

The protein encoded by this gene is cilium-specific and is required for the stability of the ciliary architecture. It is involved in the regulation of microtubule-based cilia and actin-based brush border microvilli. Mutations in this gene are associated with primary ciliary dyskinesia-13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

Primary Disease Associations & Inheritance

Ciliary dyskinesia, primary, 13MIM #613193

Active trials

Pathogenic / LP

491

ClinVar variants

Pubs (1 yr)

-2.0

Missense Z

1.00

LOEUF

Clinical Summary— DNAAF1

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Gene-Disease Validity (ClinGen)

primary ciliary dyskinesia 13 · 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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ClinVar Variants

42 Pathogenic / Likely Pathogenic· 228 VUS of 491 total submissions

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GeneReview available — DNAAF1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

1.00LOEUF

pLI 0.000

Z-score 1.56

OE 0.70 (0.50–1.00)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

-1.99Z-score

OE missense 1.28 (1.19–1.38)

502 obs / 391.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.70 (0.50–1.00)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.28 (1.19–1.38)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.17

0≤1.21.6

LoF obs/exp: 22 / 31.4Missense obs/exp: 502 / 391.4Syn Z: -1.74

0.7035th %ile

GOF

0.77top 25%

LOF

0.2679th %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.