Computational detection of copy number variation at a locus in the absence of direct measurement of the locus

A computer system to determine a copy number variant (CNV) at a locus of interest in a sample of a subject when direct measurements of copy number at the locus of interest are unavailable, the computer system comprising:

• a processor programmed to:
• access a plurality of sequence reads of a sample;
• map the plurality of sequence reads to a reference sequence, the reference sequence including a sequence of interest that includes the locus of interest;
• generate a copy number score indicating a copy number of regions along the sequence of interest, the copy number score not including a copy number at the locus of interest;
• generate a plurality of segments along the sequence of interest;
• for each segment of the plurality of segments:
• generate a respective segmented copy number score based on the segment and the copy number score;
• generate a respective weight based on historical performance of the segment in predicting a CNV at the locus of interest;
• generate a weighted score based on the respective weight and the respective segmented copy number score;
• and
• apply a probabilistic machine-learning (ML) copy number classifier to generate a probability of the CNV at the locus of interest based on an aggregate of the weighted score of each segment.