Genotype quality for assessing CNV in gnomAD SV v4?

Structural Variation
1

I hope to get help on understanding “genotype quality” for one CNV entry in gnomAD v4 (DUP_CHRY_97F6D979; [gnomAD]).

We have transitioned to use Illumina Global Diversity Array (GDA) for our CMA analysis for one year. Probably due to its more dense probe design compared to the previous 850k CMA, we started to see a 2.8 Mb gains at Yq11.223q11.23 in a few male patients (usually GRCh37 chrY:24,997,342-27,770,430, largely overlapping with AZFc).

When we searched in gnomAD SV v2.1, there is no similar or larger gains, and we reported it as VUS due to its large size. When we lifted it (GRCh38 chrY:22851195-25624283) and searched in gnomAD SV v4.1 ([gnomAD]), we see this larger 4.5 Mb gain (DUP_CHRY_97F6D979; GRCh38 chrY:21883281-26405281) at >4% in most populations. If this high frequency is real, we will reclassify the 2.8 Mb gain as benign. However, the genotype quality for this 4.5 Mb gain seems to be lower than many adjacent CNVs in gnomAD SV v4.1, and I’m not sure if this gain should be deemed as high-quality SV. From our CMA data (~300 for GDCMA, a few thousands with 850k-CMA), we never see this 4.5 Mb gain (GRCh37 chrY:24029428-28551428) in our male patients.

I would appreciate any insight on how to interpret genotype quality for CNV called in gnomAD SV v4.

Thanks,

Chen Yang
University of Michigan

2

Hey Yang,

Sorry for the delayed reply, this is a huge duplication that’s relatively common in gnomad, it took me sometime to manually review many different samples across multiple batches before I can get a clear sense of the quality. Looks to me these are real events, but some samples have mosaic duplications that they have 1.2 - 2 copy of of this chrY region, that could lead to reduced genotype quality.

Hoping that makes sense to you, but let me know if anything sounds confusing, that I can further look into the data and help answering.

Best,

Xuefang