rs33978907
Variant names:
Your query was ambiguous. Multiple possible variants found:
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
Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
HBB
NM_000518.5 3_prime_UTR
NM_000518.5 3_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.34
Genes affected
HBB (HGNC:4827): (hemoglobin subunit beta) The alpha (HBA) and beta (HBB) loci determine the structure of the 2 types of polypeptide chains in adult hemoglobin, Hb A. The normal adult hemoglobin tetramer consists of two alpha chains and two beta chains. Mutant beta globin causes sickle cell anemia. Absence of beta chain causes beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. The order of the genes in the beta-globin cluster is 5'-epsilon -- gamma-G -- gamma-A -- delta -- beta--3'. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-5225488-A-G is Pathogenic according to our data. Variant chr11-5225488-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 36332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5225488-A-G is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.38). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000525 AC: 8AN: 152238Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.0000116 AC: 10AN: 862568Hom.: 0 Cov.: 12 AF XY: 0.00000441 AC XY: 2AN XY: 453220
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GnomAD4 genome 0.0000525 AC: 8AN: 152356Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2AN XY: 74510
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:12Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 28, 2024 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 11, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 30, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 12, 2023 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 29, 2024 | 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) - |
beta Thalassemia Pathogenic:3Other:1
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 05, 2020 | 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. - |
| Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Nov 16, 2015 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 06, 2020 | - - |
Beta-thalassemia HBB/LCRB Pathogenic:1
| Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
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
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 20, 2024 | - - |
Hb SS disease Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Beta-plus-thalassemia Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 1985 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at