rs33978907
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_000518.5(HBB):c.*110T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000177 in 1,014,924 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
NM_000518.5 3_prime_UTR
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: 0.0000525 AC: 8AN: 152238Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.0000116 AC: 10AN: 862568Hom.: 0 Cov.: 12 AF XY: 0.00000441 AC XY: 2AN XY: 453220
GnomAD4 genome AF: 0.0000525 AC: 8AN: 152356Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2AN XY: 74510
ClinVar
Submissions by phenotype
not provided Pathogenic:5
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This variant is associated with the following publications: (PMID: 29669226, 1787101, 30275481, 31286593, 37745687, 35023007, 37310050, 22335963, 23590658, 21119755, 32172616, 28865746, 30842225, 18294253, 21316031, 22690826, 4018033) -
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. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of multiple amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs33978907, gnomAD 0.03%). This variant has been observed in individuals with beta-thalassemia (PMID: 1787101, 4018033, 22335963, 22690826, 23590658). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36332). Studies have shown that this variant results in the activation of a cryptic splice site in 3' UTR (PMID: 4018033). For these reasons, this variant has been classified as Pathogenic. -
The HBB c.*110T>C variant (rs33978907, HbVar ID: 968), also known as Poly A (T->C), has been reported in multiple patients diagnosed with beta (+) thalassemia, and has been found in a homozygous state, or in-trans with other pathogenic variants (Hoppe 2013, Italia 2012, Orkin 1985, Sinha 2009, Sivalingam 2012, see link to HbVar). Functional characterization of the variant indicates the loss of the canonical polyadenylation site, resulting in an elongated HBB transcript that is less efficiently processed by a downstream cryptic polyadenylation site (Orkin 1985). This variant is listed as pathogenic by multiple laboratories in ClinVar (Variation ID: 36332), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant is located in a conserved region of the 3' UTR, and computational algorithms (Poly A miner) predict an impact on the transcript, consistent with observations from the functional study. Based on available information, the c.*110T>C variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Hoppe CC. Prenatal and newborn screening for hemoglobinopathies. Int J Lab Hematol. 2013 Jun;35(3):297-305. PMID: 23590658. Italia K et al. Variable haematological and clinical presentation of beta-thalassaemia carriers and homozygotes with the Poly A (T?C) mutation in the Indian population. Eur J Haematol. 2012; 89(2):160-4. PMID: 22690826. 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. Sinha S et al. Profiling beta-thalassaemia mutations in India at state and regional levels: implications for genetic education, screening and counselling programmes. Hugo J. 2009 Dec;3(1-4):51-62. PMID: 21119755. Sivalingam M et al. Molecular study and genotype/phenotype correlation of beta thalassemia in Malaysia. Int J Lab Hematol. 2012 Aug;34(4):377-82. PMID: 22335963. -
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beta Thalassemia Pathogenic:3Other:1
Variant summary: HBB c.*110T>C is located in the 3UTR downstream of the termination codon involves the alteration of a conserved nucleotide. The variant of interest is located within the known "polyA' tail, thus expected to alter mRNA expression, which is supported by Orkin_1985 functional findings. The variant allele was found at a frequency of 6.4e-05 in 31396 control chromosomes (gnomAD), which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.011). c.*110T>C has been reported in the literature in multiple individuals affected with Beta Thalassemia and implicated to be the third most common allele in India (Orkin_1985, Sinha_2009, Italia_2012). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (4x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic. -
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Beta-thalassemia HBB/LCRB 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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Hb SS disease 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