ClinVar Genomic variation as it relates to human health

This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. Found in at least one patient with expected phenotype for this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.

Published functional studies demonstrate a damaging effect: reduced beta-globin RNA compared to wildtype (Antonarakis et al., 1984; Calvo et al., 2009); Also known as c.-29 A>G using alternate nomenclature; This variant is associated with the following publications: (PMID: 2458145, 30275481, 22975760, 19372376, 6583702, 2123063, 2014803, 8435318, 3021607, 8330981, 28366028, 28385923, 31395865, 31589614, 32746448)

The HBB c.-79A>G variant (rs34598529, HbVar ID: 767), also known as -29 (A>G), is reported in the literature in multiple patients with beta (+) thalassemia, and has been found in a homozygous state or in-trans with another pathogenic HBB variant (Antonarakis 1984, Carrocini 2017, Huang 1986, Ropero 2017, HbVar database and references therein). Functional characterization of this variant indicates a significant reduction of beta globin transcription to 25 percent of normal levels (Antonarakis 1984). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 15469), and is found in the African population with an allele frequency of 0.32% (28/8,704 alleles) in the Genome Aggregation Database. The variant lies in the conserved proximal promoter of HBB, and is predicted to affect transcription factor binding. Based on available information, the c.-79A>G variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Antonarakis S et al. beta-Thalassemia in American Blacks: novel mutations in the "TATA" box and an acceptor splice site. Proc Natl Acad Sci U S A. 1984 81(4):1154-8. PMID: 6583702. Carrocini GCS et al. Mutational Profile of Homozygous B-Thalassemia in Rio de Janeiro, Brazil. Hemoglobin. 2017 Jan;41(1):12-15. PMID: 28366028. Huang S et al. The same "TATA" box beta-thalassemia mutation in Chinese and US blacks: another example of independent origins of mutation. Hum Genet. 1986 74(2):162-4. PMID: 3021607. Ropero P et al. Phenotype of mutations in the promoter region of the B-globin gene. J Clin Pathol. 2017 Oct;70(10):874-878. PMID: 28385923.

This variant occurs in a non-coding region of the HBB gene. It does not change the encoded amino acid sequence of the HBB protein. This variant is present in population databases (rs34598529, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individuals with autosomal recessive beta thalassemia (PMID: 2123063, 2458145, 3021607, 6583702, 28385923). It has also been observed to segregate with disease in related individuals. This variant is also known as c.-29A>G . Studies have shown that this variant alters HBB gene expression (PMID: 6583702). For these reasons, this variant has been classified as Pathogenic.

Variant summary: The c.-79A>G variant affects a conserved nucleotide in TATA box in 5'UTR. One in-silico tool predicts damaging outcome for this variant. This variant is found in 2/5008 control chromosomes at a frequency of 0.0003994, which does not exceed maximal expected frequency of a pathogenic allele (0.0111803). In functional studies the variant of interest was shown to reduce the production of the b-globin mRNA. This change is a widely accepted to be deleterious and multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.

NM_000518.4(HBB):c.-79A>G(aka -29A>G) is classified as pathogenic and is associated with beta thalassemia. Sources cited for classification include the following: PMID: 2458145, and 6583702. Classification of NM_000518.4(HBB):c.-79A>G(aka -29A>G) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

The c.-79A>G pathogenic mutation (also known as -29A>G) is located in the 5' untranslated region (5&rsquo; UTR) of the HBB gene. This pathogenic mutation results from an A to G substitution 79 bases upstream from the first translated codon. In one study, this mutation was confirmed to be homozygous in an African American female with mild beta-thalassemia, whose mother was confirmed to be a heterozygous carrier. In addition, in vitro studies showed a mild reduction in beta-globin RNA transcripts (75% of wild-type) (Antonarakis SE et al. Proc. Natl. Acad. Sci. U.S.A. 1984;81(4):1154-8). In a luciferase reporter assay, a moderate reduction in mRNA was observed in addition to a significant decrease in protein levels (p <2e-12) in cells transfected with c.-79A>G (Calvo SE et al. Proc. Natl. Acad. Sci. U.S.A., 2009 May;106:7507-12). This mutation is one of the most common HBB mutations and has been observed in numerous Chinese and African American newborns with clinically significant beta-thalassemia ascertained through California's newborn screening program (Hoppe CC et al. Int J Lab Hematol 2013; 35(3):297-305). Based on the supporting evidence, c.-79A>G is interpreted as a disease-causing mutation.