11-5227100-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The ENST00000647020.1(HBB):c.-79A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000173 in 1,010,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
ENST00000647020.1 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000821 AC: 125AN: 152186Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.0000571 AC: 49AN: 858236Hom.: 0 Cov.: 12 AF XY: 0.0000378 AC XY: 17AN XY: 450228
GnomAD4 genome AF: 0.000827 AC: 126AN: 152304Hom.: 0 Cov.: 33 AF XY: 0.000859 AC XY: 64AN XY: 74474
ClinVar
Submissions by phenotype
not provided Pathogenic:5
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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. -
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 (also known as -29A>G) has been reported in published literature in affected individuals with beta(+)-thalassemia (PMIDs: 28385923 (2017), 26079343 (2015), 18294253 (2008), 9401495 (1997), 2458145 (1988)). The frequency of this variant in the general population, 0.0032 (28/8704 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. Genetic counseling and testing of at-risk relatives are recommended. -
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. -
beta Thalassemia Pathogenic:4Other:1
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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. -
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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. -
Inborn genetic diseases Pathogenic:1
The c.-79A>G alteration is located in the 5' untranslated region (5'UTR) of the HBB gene. This alteration consists of a A to G substitution 79 nucleotides upstream from the first translated codon. Based on data from gnomAD, the G allele has an overall frequency of 0.089% (28/31390) total alleles studied. The highest observed frequency was 0.322% (28/8704) of African alleles. This variant, also known as -29A>G, has been identified in the homozygous state and/or in conjunction with other HBB variants in individuals with mild or major beta-thalassemia (Antonarakis, 1984; Gonzalez-Redondo, 1988; Ropero, 2017). This variant 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, 2013). Multiple functional studies show this variant leads to a reduction of mRNA (Antonarakis, 1984; Calvo, 2009). Based on the available evidence, this alteration is classified as pathogenic. -
Heinz body anemia Pathogenic:1
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Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:METHEMOGLOBINEMIA, BETA TYPE;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6;CN322236:Beta-thalassemia HBB/LCRB Pathogenic:1
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Beta-plus-thalassemia Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at