Mosaic Detection
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The default mode of the small variant caller has been optimized to detect germline variants with typical AFs of 0%, 50% or 100%. Non-cancer post-zygotic mosaic variants have typical allele frequencies (AFs) lower than 50% and therefore more challenging to find with the default small variant caller. To improve sensitivity of low AF calls, a new machine learning (ML) model trained using read and context evidence from low AF calls is used. This allows the model to identify variants down to approximately 5% AF on 35x WGS and 3% AF on 300x WGS. The mosaic ML model is applied to all calls that are rejected by the germline model and variants detected with the mosaic detection are identified by a MOSAIC
flag in the VCF INFO field.
MOSAIC
tagged variants with QUAL
smaller than 3.0103
are filtered with the MosaicHardQUAL
filter.
We provide an optional MosaicLowAF
filtering option to filter MOSAIC
tagged variants with AF
smaller than the AF
threshold. The threshold for this filter can be set with the --vc-mosaic-af-filter-threshold
option. The default value for the mosaic AF
filter threshold is set to 0.2
if the median depth of the sample detected by the ploidy caller is <= 100x
and 0.1
if the detected depth is >100x
. All MOSAIC
variants can be reported, regardless of their AF
, with the --vc-mosaic-af-filter-threshold=0
option. For haploid regions, we apply separate handling that uses a threshold of 0.75
for assigning MOSAIC
tags. Please refer to the section for more details.
Furthermore, the output of MOSAIC
tagged calls can be restricted using an optional target BED provided with the --vc-mosaic-target-bed
option.
--vc-enable-mosaic-detection
Set to true to enable mosaic detection. Set to false to disable mosaic detection.
--vc-mosaic-af-filter-threshold
Set the allele frequency threshold for the application of the MosaicLowAF
filter to mosaic calls. All MOSAIC
tagged variants with AF
smaller than the AF
threshold are filtered with the MosaicLowAF
filter. The default mosaic AF
filter threshold is set to 0.2
if the median depth of the sample detected by the ploidy caller is <= 100x
and 0.1
if the detected depth is > 100x
.
--vc-mosaic-qual-filter-threshold
Set the QUAL
threshold for the application of the MosaicHardQUAL
filter to mosaic calls. All MOSAIC
tagged variants with QUAL
smaller than the threshold QUAL
are filtered with the MosaicHardQUAL
filter. The default mosaic QUAL
filter threshold is set to 3.0103
.
--vc-mosaic-target-bed
Optional target BED file to restrict the output of MOSAIC
tagged variant calls only in the specified regions.
Small variant calling features comparison between default germline small variant caller and mosaic detection mode in DRAGEN 4.2, DRAGEN 4.3 and DRAGEN 4.4
4.2
DRAGEN 4.2 default Small Variant Caller
--enable-variant-caller=true
3
No
No
N/A
4.2 HSM
DRAGEN 4.2 High Sensitivity Mode
--enable-variant-caller=true --vc-enable-high-sensitivity-mode=true
0.4
Yes
Yes (Alpha)
N/A
4.3
DRAGEN 4.3 default Small Variant Caller
--enable-variant-caller=true
3
Yes
Yes (Full)
20%
4.3 Mosaic
DRAGEN 4.3 Mosaic Detection Mode
--enable-variant-caller=true --vc-enable-mosaic-detection=true
0.4
Yes
Yes (Full)
0%
4.4
DRAGEN 4.4 default Small Variant Caller
--enable-variant-caller=true
3.0103
Yes
Yes (Full)
20% if depth <=100x, 10% otherwise
4.4
DRAGEN 4.4 default Small Variant Caller
--enable-variant-caller=true --vc-enable-mosaic-detection=true
3.0103
Yes
Yes (Full)
20% if depth <=100x, 10% otherwise
4.4 Mosaic
DRAGEN 4.4 Mosaic Detection Mode
--enable-variant-caller=true --vc-enable-mosaic-detection=true --vc-mosaic-af-filter-threshold=0
3.0103
Yes
Yes (Full)
0%
The command line behavior of --vc-enable-mosaic-detection=true
has changed between DRAGEN 4.3 and DRAGEN 4.4. In DRAGEN 4.3, explicitly setting --vc-enable-mosaic-detection=true
caused two changes to default behavior:
The hard filter QUAL
threshold for both SNPs and INDELs is lowered to 0.4
in this mode to allow low AF calls to be set as PASS
in the FILTER field.
The mosaic AF
filter threshold is set to 0.0
.
In DRAGEN 4.4, to improve the user experience, both these changes have been decoupled from the --vc-enable-mosaic-detection=true
option, therefore the user can report all MOSAIC
variants, regardless of their AF
, with the --vc-mosaic-af-filter-threshold=0
option.