Analyzing globin gene variation in gnomAD: implications for variant interpretation in hemoglobinopathies

Abstract

Background Given the augmented sampling and ancestry stratification of the Genome Aggregation Database (gnomAD) v4.1 compared to v2.1.1, population evidence for globin gene variants was assessed for changes in the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) criteria fulfillment, which can alter downstream variant interpretation. Methods Variants and constraint metrics for -globin locus genes HBA1, HBA2, and HBZ, and {beta}-globin locus genes HBB, HBD, HBG1, HBG2, and HBE1, were extracted from gnomAD v2.1.1 and v4.1 callsets, harmonized, matched to ClinVar annotations, and evaluated against BA1, BS1, BS2, BS2_Supporting, and PM2_Supporting ACMG/AMP criteria using Clinical Genome Resource Hemoglobinopathy Variant Curation Expert Panel thresholds. Results Globin gene variants increased fourfold across gnomAD releases, with HBB contributing the largest share. In v4.1, 68.7% of quality-passing variants were ancestry-specific, 14.4% overlapped ClinVar and PM2_Supporting fulfillment rose from 81.5% to 93.5%. Among variants present in both releases, ACMG/AMP population-criterion assessments were largely concordant, with conflicting combinations in <1%. Conclusions Leveraging augmented sampling and improved ancestry representation, gnomAD v4.1 increased globin gene variant discovery, particularly for rare variants, enabling more precise allele frequency estimates and robust assessment of BA1, BS1, and PM2_Supporting, although criterion fulfillment remains release- and callset-specific.