Objectives The implementation of chromosomal microarray analysis (CMA) in prenatal testing for all patients has not achieved a consensus. Technical alternatives such as Prenatal BACs‐on‐BeadsTM (PNBoBsTM) have thus been applied. The aim of this study was to provide the frequencies of the submicroscopic defects detectable by PNBoBsTM under different prenatal indications. Methods A total of 9648 prenatal samples were prospectively analyzed by karyotyping plus PNBoBsTM and classified by prenatal indication. The frequencies of the genomic defects and their 95%CIs were calculated for each indication. Results The overall incidence of cryptic imbalances was 0.7%. The majority involved the DiGeorge syndrome critical region (DGS). The additional diagnostic yield of PNBoBsTM in the population with a low a priori risk was 1/298. The prevalences of DGS microdeletion and microduplication in the low‐risk population were 1/992 and 1/850, respectively. Conclusions The constant a priori risk for common pathogenic cryptic imbalances detected by this technology is estimated to be ~0.3%. A prevalence higher than that previously estimated was found for the 22q11.2 microdeletion. Their frequencies were independent of maternal age. These data have implications for cell‐free DNA screening tests design and justify prenatal screening for 22q11 deletion, as early recognition of DGS improves its prognosis. © 2015 John Wiley & Sons, Ltd. What's already known about this topic? Common pathogenic microdeletion/microduplication syndromes detectable by PNBoBsTM have an estimated prevalence of 1/250 in low‐risk pregnancies. The discovery in the maternal circulation of cell‐free placental DNA (cfDNA) revolutionized non‐invasive prenatal screening for common aneuploidies. However, microdeletions/duplications may result in disabilities that can be more severe than certain aneuploidies. Consistent results about the prevalences of common pathogenic cryptic imbalances in low‐risk populations are lacking. What does this study add? The frequencies of submicroscopic defects (including 22q11.2 microdeletions and microduplications) under different prenatal indications, particularly in the low‐risk prenatal population, are provided. The a priori risk for common pathogenic cryptic imbalances was estimated to be ~0.3%. The assumption that submicroscopic genomic imbalances are not maternal age dependent is demonstrated. Implications for the development of cfDNA‐based screening are discussed.