ArticleAmerican journal of human genetics2021
Exome variant discrepancies due to reference-genome differences.
Article in American journal of human genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 63 citations in OpenAlex.
- Taming the reference genome jungle: the refget sequence collection standard.Bioinformatics (Oxford, England) · 2026Article
- Atlas of glomerular disease-specific genetic effects on blood transcriptome.medRxiv : the preprint server for health sciences · 2026Article
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- Revealing the Potential Associations of Mutation-Related Genes with Lymph Node Metastasis in Gallbladder Cancer Through Transcriptome and Exome Sequencing.Biomedicines · 2026Article
- African Pan Genome Contigs Expose Biologically Relevant Sequence Still Hidden from Human Reference Frameworks.bioRxiv : the preprint server for biology · 2026Article
- An integrated platform for concurrent structural and single-nucleotide variants improves copy-number detection and reveals pathogenic alleles in undiagnosed Mendelian families.Genome medicine · 2025Article
- GREGoR: accelerating genomics for rare diseases.Nature · 2025Article
- Differences in GenBank and RefSeq annotations may affect genomics data interpretation formSphere · 2025Article
- Recommendations for bioinformatics in clinical practice.Genome medicine · 2025Review
- Taming the reference genome jungle: the refget sequence collection standard.bioRxiv : the preprint server for biology · 2025Article
- Whole-genome sequencing resources of 301 indigenous Tibetan sheep from the Himalayan region.Scientific data · 2025Article
- Congenital enteropathy caused by ezrin deficiency.Human genetics · 2025Article
- Evolution, genetic diversity, and health.Nature medicine · 2025Review
- Beyond single references: pangenome graphs and the future of genomic medicine.Frontiers in genetics · 2025Review
- Laboratory considerations for GRCh37 to GRCh38 reference genome transition: A laboratory quality assurance bulletin of the American College of Medical Genetics and Genomics (ACMG).Genetics in medicine open · 2025Article
- GREGoR: Accelerating Genomics for Rare Diseases.ArXiv · 2024Article
- StableLift: Optimized Germline and Somatic Variant Detection Across Genome Builds.bioRxiv : the preprint server for biology · 2024Article
- VizCNV: An integrated platform for concurrent phased BAF and CNV analysis with trio genome sequencing data.bioRxiv : the preprint server for biology · 2024Article
- Characterization and distribution of de novo mutations in the zebra finch.Communications biology · 2024Article
- Unraveling the genomic diversity and admixture history of captive tigers in the United States.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
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Authors and funding
13 authors at 3 institutions in 1 country.
Funding
Abstract
Despite release of the GRCh38 human reference genome more than seven years ago, GRCh37 remains more widely used by most research and clinical laboratories. To date, no study has quantified the impact of utilizing different reference assemblies for the identification of variants associated with rare and common diseases from large-scale exome-sequencing data. By calling variants on both the GRCh37 and GRCh38 references, we identified single-nucleotide variants (SNVs) and insertion-deletions (indels) in 1,572 exomes from participants with Mendelian diseases and their family members. We found that a total of 1.5% of SNVs and 2.0% of indels were discordant when different references were used. Notably, 76.6% of the discordant variants were clustered within discrete discordant reference patches (DISCREPs) comprising only 0.9% of loci targeted by exome sequencing. These DISCREPs were enriched for genomic elements including segmental duplications, fix patch sequences, and loci known to contain alternate haplotypes. We identified 206 genes significantly enriched for discordant variants, most of which were in DISCREPs and caused by multi-mapped reads on the reference assembly that lacked the variant call. Among these 206 genes, eight are implicated in known Mendelian diseases and 53 are associated with common phenotypes from genome-wide association studies. In addition, variant interpretations could also be influenced by the reference after lifting-over variant loci to another assembly. Overall, we identified genes and genomic loci affected by reference assembly choice, including genes associated with Mendelian disorders and complex human diseases that require careful evaluation in both research and clinical applications.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.