{ "schema_version": "1.0", "generated_date": "2026-08-01", "purpose": "Reproducible evidence linking Phase 3 exome BAMs to same-sample Phase 3 SV calls, later 30x WGS ensemble calls, and public DRAGEN CNV/SV calls for BRCA exon-level deletion validation.", "references": { "phase3_sv_vcf_grch37": "https://ftp.1000genomes.ebi.ac.uk/vol1/ftp/phase3/integrated_sv_map/ALL.wgs.mergedSV.v8.20130502.svs.genotypes.vcf.gz", "phase3_sv_vcf_grch37_tbi": "https://ftp.1000genomes.ebi.ac.uk/vol1/ftp/phase3/integrated_sv_map/ALL.wgs.mergedSV.v8.20130502.svs.genotypes.vcf.gz.tbi", "phase3_sv_readme": "https://ftp.1000genomes.ebi.ac.uk/vol1/ftp/phase3/integrated_sv_map/README_phase3_sv_callset_20150224", "high_coverage_sequence_index": "https://ftp.1000genomes.ebi.ac.uk/vol1/ftp/data_collections/1000G_2504_high_coverage/1000G_2504_high_coverage.sequence.index", "high_coverage_sv_vcf_grch38": "https://ftp.1000genomes.ebi.ac.uk/vol1/ftp/data_collections/1000G_2504_high_coverage/working/20210124.SV_Illumina_Integration/1KGP_3202.gatksv_svtools_novelins.freeze_V3.wAF.vcf.gz", "high_coverage_sv_vcf_grch38_tbi": "https://ftp.1000genomes.ebi.ac.uk/vol1/ftp/data_collections/1000G_2504_high_coverage/working/20210124.SV_Illumina_Integration/1KGP_3202.gatksv_svtools_novelins.freeze_V3.wAF.vcf.gz.tbi", "high_coverage_paper": "https://doi.org/10.1016/j.cell.2022.08.004", "dragen_registry": "https://registry.opendata.aws/ilmn-dragen-1kgp/", "dragen_v3_5_7b_manifest": "https://1000genomes-dragen.s3.amazonaws.com/1000genomes-dragen__dragen-3.5.7b__hg38_altaware_nohla__germline.json", "brca1_mane_transcript": "ENST00000357654", "brca1_mane_lookup": "https://rest.ensembl.org/lookup/id/ENST00000357654?expand=1;content-type=application/json" }, "cohort_match_and_remote_access": { "current_exome_inventory_samples": 150, "phase3_sv_vcf_sample_columns": 2504, "current_ids_found_in_phase3_sv_vcf": 150, "high_coverage_sequence_index_rows": 2504, "high_coverage_sequence_index_unique_samples": 2504, "current_ids_found_in_high_coverage_sequence_index": 150, "current_ids_missing_from_high_coverage_sequence_index": 0, "cram_index_suffix": ".cram.crai", "http_range_supported": true, "http_range_test_status": 206, "interpretation": "All 150 current Phase 3 exome sample IDs have later same-person 30x WGS CRAMs and genotypes online. BAM/CRAM and VCF servers support indexed byte-range queries, so BRCA-only extraction does not require complete-file download." }, "query_scope": { "brca1_grch38_mane_interval_1based": "chr17:43044295-43125364", "brca1_mane_exon_source": "Ensembl lookup for ENST00000357654", "phase3_brca1_grch37_interval_queried_1based": "17:41196312-41277500", "brca2_grch38_interval_queried_1based": "chr13:32315086-32400266", "brca2_grch37_interval_queried_1based": "13:32889611-32973805" }, "samples": [ { "sample_id": "NA18949", "in_current_150": false, "classification": "BRCA1 two-exon heterozygous deletion positive", "phase3_exome": { "bam_url": "https://ftp.1000genomes.ebi.ac.uk/vol1/ftp/phase3/data/NA18949/exome_alignment/NA18949.mapped.ILLUMINA.bwa.JPT.exome.20121211.bam", "bai_url": "https://ftp.1000genomes.ebi.ac.uk/vol1/ftp/phase3/data/NA18949/exome_alignment/NA18949.mapped.ILLUMINA.bwa.JPT.exome.20121211.bam.bai", "bam_bytes": 11042427115, "bam_http_range_status": 206, "bai_head_status": 200 }, "phase3_sv_grch37": { "id": "SI_BD_15305", "chrom": "17", "pos": 41221932, "end": 41227605, "svtype": "DEL", "filter": "PASS", "genotype": "0|1", "carrier_count": 1, "source": "DEL_union" }, "high_coverage_cram": { "run_id": "ERR3239399", "cram_url": "https://ftp.sra.ebi.ac.uk/vol1/run/ERR323/ERR3239399/NA18949.final.cram", "crai_url": "https://ftp.sra.ebi.ac.uk/vol1/run/ERR323/ERR3239399/NA18949.final.cram.crai", "cram_bytes": 16008083610, "crai_bytes": 1352869 }, "high_coverage_ensemble_grch38": { "id": "HGSV_216997", "chrom": "chr17", "pos": 43069993, "end": 43075601, "svlen": -5608, "svtype": "DEL", "filter": "PASS", "genotype": "0/1", "carrier_count": 1, "algorithms": ["depth", "manta"], "evidence": ["PE", "RD", "SR"] }, "dragen_v3_5_7b": { "cnv_vcf_url": "https://1000genomes-dragen.s3.amazonaws.com/data/dragen-3.5.7b/hg38_altaware_nohla-cnv-anchored/NA18949/NA18949.cnv.vcf.gz", "cnv_vcf_bytes": 22379, "cnv_record": { "id": "DRAGEN:LOSS:chr17:43069490-43076906", "vcf_pos": 43069489, "end": 43076906, "filter": "cnvLength", "genotype": "0/1", "copy_number": 1 }, "sv_vcf_url": "https://1000genomes-dragen.s3.amazonaws.com/data/dragen-3.5.7b/hg38_altaware_nohla-cnv-anchored/NA18949/NA18949.sv.vcf.gz", "sv_vcf_bytes": 1176351, "sv_record": { "id": "MantaDEL:10638:0:1:0:0:0", "chrom": "chr17", "pos": 43069972, "end": 43075601, "svlen": -5629, "svtype": "DEL", "filter": "PASS", "genotype": "0/1", "genotype_quality": 496 } }, "mane_exon_overlap": { "exon_count": 2, "exons_grch38_1based": ["chr17:43070928-43071238", "chr17:43074331-43074521"] }, "cross_callset_agreement": "Phase 3 PASS DEL, later 30x ensemble PASS DEL, and DRAGEN Manta PASS DEL agree on one heterozygous event. DRAGEN depth CNV also reports CN=1 but is flagged cnvLength rather than PASS." }, { "sample_id": "HG01528", "in_current_150": false, "classification": "BRCA1 six-exon heterozygous deletion positive", "phase3_exome": { "bam_url": "https://ftp.1000genomes.ebi.ac.uk/vol1/ftp/phase3/data/HG01528/exome_alignment/HG01528.mapped.ILLUMINA.bwa.IBS.exome.20121211.bam", "bai_url": "https://ftp.1000genomes.ebi.ac.uk/vol1/ftp/phase3/data/HG01528/exome_alignment/HG01528.mapped.ILLUMINA.bwa.IBS.exome.20121211.bam.bai", "bam_bytes": 10319084612, "bam_http_range_status": 206, "bai_head_status": 200 }, "phase3_sv_grch37": null, "high_coverage_cram": { "run_id": "ERR3241935", "cram_url": "https://ftp.sra.ebi.ac.uk/vol1/run/ERR324/ERR3241935/HG01528.final.cram", "crai_url": "https://ftp.sra.ebi.ac.uk/vol1/run/ERR324/ERR3241935/HG01528.final.cram.crai", "cram_bytes": 15406344321, "crai_bytes": 1321173 }, "high_coverage_ensemble_grch38": { "id": "HGSV_217000", "chrom": "chr17", "pos": 43102678, "end": 43183624, "svlen": -80946, "svtype": "DEL", "filter": "PASS", "genotype": "0/1", "carrier_count": 1, "algorithms": ["depth", "manta"], "evidence": ["BAF", "PE", "RD", "SR"] }, "dragen_v3_5_7b": { "cnv_vcf_url": "https://1000genomes-dragen.s3.amazonaws.com/data/dragen-3.5.7b/hg38_altaware_nohla-cnv-anchored/HG01528/HG01528.cnv.vcf.gz", "cnv_vcf_bytes": 22156, "cnv_record": { "id": "DRAGEN:LOSS:chr17:43102091-43183034", "vcf_pos": 43102090, "end": 43183034, "filter": "PASS", "genotype": "0/1", "copy_number": 1 }, "sv_vcf_url": "https://1000genomes-dragen.s3.amazonaws.com/data/dragen-3.5.7b/hg38_altaware_nohla-cnv-anchored/HG01528/HG01528.sv.vcf.gz", "sv_vcf_bytes": 1172848, "sv_record": { "id": "MantaDEL:10758:0:1:0:0:0", "chrom": "chr17", "pos": 43102676, "end": 43183624, "svlen": -80948, "svtype": "DEL", "filter": "PASS", "genotype": "0/1", "genotype_quality": 572 } }, "mane_exon_overlap": { "exon_count": 6, "exons_grch38_1based": [ "chr17:43104122-43104261", "chr17:43104868-43104956", "chr17:43106456-43106533", "chr17:43115726-43115779", "chr17:43124017-43124115", "chr17:43125271-43125364" ] }, "cross_callset_agreement": "Later 30x ensemble PASS DEL, DRAGEN Manta PASS DEL, and DRAGEN depth CNV PASS CN=1 agree on one heterozygous multi-exon event. The event was not present in the older Phase 3 SV callset." }, { "sample_id": "HG02601", "in_current_150": true, "classification": "small intronic BRCA1 deletion; negative for exon-level LGA", "phase3_exome": { "bam_url": "https://ftp.1000genomes.ebi.ac.uk/vol1/ftp/phase3/data/HG02601/exome_alignment/HG02601.mapped.ILLUMINA.bwa.PJL.exome.20121211.bam", "bai_url": "https://ftp.1000genomes.ebi.ac.uk/vol1/ftp/phase3/data/HG02601/exome_alignment/HG02601.mapped.ILLUMINA.bwa.PJL.exome.20121211.bam.bai", "bam_bytes": 7898198294, "bam_http_range_status": 206, "bai_head_status": 200 }, "phase3_sv_grch37": null, "high_coverage_cram": { "run_id": "ERR3242400", "cram_url": "https://ftp.sra.ebi.ac.uk/vol1/run/ERR324/ERR3242400/HG02601.final.cram", "crai_url": "https://ftp.sra.ebi.ac.uk/vol1/run/ERR324/ERR3242400/HG02601.final.cram.crai", "cram_bytes": 15275521140, "crai_bytes": 1338757 }, "high_coverage_ensemble_grch38": { "id": "HGSV_216996", "chrom": "chr17", "pos": 43045958, "end": 43046229, "svlen": -271, "svtype": "DEL", "filter": "PASS", "genotype": "0/1", "carrier_count": 3, "source": "svtools" }, "dragen_v3_5_7b": { "cnv_vcf_url": "https://1000genomes-dragen.s3.amazonaws.com/data/dragen-3.5.7b/hg38_altaware_nohla-cnv-anchored/HG02601/HG02601.cnv.vcf.gz", "cnv_vcf_bytes": 22971, "cnv_record": null, "sv_vcf_url": "https://1000genomes-dragen.s3.amazonaws.com/data/dragen-3.5.7b/hg38_altaware_nohla-cnv-anchored/HG02601/HG02601.sv.vcf.gz", "sv_vcf_bytes": 1199329, "sv_record": { "id": "MantaDEL:11233:0:0:0:0:0", "chrom": "chr17", "pos": 43045922, "end": 43046229, "svlen": -307, "svtype": "DEL", "filter": "PASS", "genotype": "0/1", "genotype_quality": 121 } }, "mane_exon_overlap": { "exon_count": 0, "location": "between chr17:43044295-43045802 and chr17:43047643-43047703" }, "cross_callset_agreement": "Later 30x ensemble and DRAGEN Manta agree on a small intronic deletion. DRAGEN CNV reports no BRCA1 CNV. This is not an exon-level positive." } ], "validation_summary": { "current_150_known_brca_exon_deletion_or_duplication_positives": 0, "additional_same-project_online_brca1_exon_deletion_positives": 2, "additional_positive_ids": ["NA18949", "HG01528"], "confirmed_brca1_duplication_positives": 0, "confirmed_brca2_exon_deletion_or_duplication_positives": 0, "recommended_use": "Use NA18949 and HG01528 as remote positive WES cases and the current 150 as primarily negative controls. Treat HG02601 as a hard intronic negative for exon-level classification." }, "limitations": [ "The Phase 3 and 30x/DRAGEN callsets are population research callsets, not clinical truth sets.", "The 30x ensemble and DRAGEN results use the same later WGS reads but different callers; they are computationally corroborating, not independent biological replicates.", "All samples derive from lymphoblastoid cell lines, so cell-line mosaic or culture-acquired events are possible.", "Two deletion positives and zero duplication positives are insufficient to estimate clinical sensitivity; broader orthogonally validated positive cohorts and synthetic exon deletions/duplications remain necessary." ] }