DNAH3

Chr 16

dynein axonemal heavy chain 3

Also known as: DNAHC3-B, DNAHC3B, HDHC8, HEL-36, HSADHC3

NCBI Gene: 55567 ENSG00000158486 UniProt: Q8TD57 OMIM: 603334

The DNAH3 protein is an axonemal dynein heavy chain that generates force for ciliary and flagellar beating through ATP hydrolysis, essential for respiratory cilia function and sperm motility. Mutations cause primary ciliary dyskinesia with male infertility, affecting the respiratory system and reproductive function. This condition follows autosomal recessive inheritance.

OMIM ResearchSummary from RefSeq, UniProt

This gene belongs to the dynein family, whose members encode large proteins that are constituents of the microtubule-associated motor protein complex. This complex is composed of dynein heavy, intermediate and light chains, which can be axonemal or cytoplasmic. This protein is an axonemal dynein heavy chain. It is involved in producing force for ciliary beating by using energy from ATP hydrolysis. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Dec 2016]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.80

Clinical Summary— DNAH3

⚡

Population Constraint (gnomAD)

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

📋

ClinVar Variants

4 unique Pathogenic / Likely Pathogenic· 666 VUS of 789 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.80LOEUF

pLI 0.000

Z-score 3.96

OE 0.69 (0.60–0.80)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.03Z-score

OE missense 1.00 (0.96–1.03)

2256 obs / 2260.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.69 (0.60–0.80)

0≤0.351.4

Missense OE?1.00 (0.96–1.03)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 132 / 191.1Missense obs/exp: 2256 / 2260.0Syn Z: -2.13

This gene — mechanism propensity

0.6356th %ile

GOF

0.74top 25%

LOF

0.2386th %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.

ClinVar Variant Classifications

789 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic3

VUS666

Likely Benign61

Benign18

Conflicting5

Pathogenic

Likely Pathogenic

666

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	1	2	0	0	3
VUS	4	660	1	1	666
Likely Benign	0	39	2	20	61
Benign	0	4	3	11	18
Conflicting	—				5
Total	5	706	6	32	754

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

14 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap DNAH3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →