ClinVar Genomic variation as it relates to human health

Variant summary: HBB c.*110_*111delTA is located in the untranslated mRNA region downstream of the termination codon that lies in the 'known' polyA tail signal (AATAAA) of HBB, and mutations in this region are known to reduce the synthesis of mRNA. Therefore, this variant is expected or likely to interfere with cleavage of transcript and addition of polyA tail, leading to an elongated transcript that is unstable (Orkin 1985). The variant allele was found at a frequency of 5.9e-06 in 1015192 control chromosomes (gnomAD database v4). c.*110_*111delTA has been reported twice in literature, one individual diagnosed with BTHAL and one individual having typical features of BTHAL minor (Ghanem_1992, Kimberland_1995). Ithanet lists variant as a "Globin gene causative mutation". In the same region, a variant c.*110T>C and c.*111A>G have been reported in literature as a common pathogenic variants. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 1301930, 21423179, 7599641). ClinVar contains an entry for this variant (Variation ID: 632843). Based on the evidence outlined above, the variant was classified as likely pathogenic.

The variant disrupts the canonical polyadenylation signal, and is therefore predicted to result in the loss of a functional protein. The variant is found in at least one symptomatic individual, and not found in general population data.

The Poly A (-AT or -TA) variant (HBB: *110_*111delTA, rs63750205, HbVar ID: 972) is reported in an individual with beta-thalassemia and in an individual presenting with typical beta-thalassemia trait (Ghanem 1992, HbVar link, Kimberland 1995). This variant is also listed in ClinVar (Variation ID: 632843), and in ITHANET as a causative variant (ITHANET link). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant is located in the untranslated mRNA region in the known polyA tail signal (AATAAA) of HBB. Other variants in this region (c.*110T>C, c.*111A>G) are common pathogenic variants shown to reduce mRNA synthesis (Orkin 1985). Based on available information, the *110_*111delTA variant is considered to be likely pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Link to ITHANET database: https://www.ithanet.eu/db/ithagenes?ithaID=277 Ghanem N et al. A comprehensive scanning method for rapid detection of beta-globin gene mutations and polymorphisms. Hum Mutat. 1992;1(3):229-39. PMID: 1301930. Kimberland ML, Boehm CD, Kazazian HH Jr. Two novel beta-thalassemia alleles: poly A signal (AATAAA-->AAAA) and -92 C-->T. Hum Mutat. 1995;5(3):275-6. PMID: 7599641. Orkin S et al. Thalassemia due to a mutation in the cleavage-polyadenylation signal of the human beta-globin gene. EMBO J. 1985; 4(2):453-6. PMID: 4018033.