11-5225466-G-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_000518.5(HBB):c.*132C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000176 in 850,534 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000057 ( 0 hom. )
Consequence
HBB
NM_000518.5 3_prime_UTR
NM_000518.5 3_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.114
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_benign. Variant got -2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBB | NM_000518.5 | c.*132C>A | 3_prime_UTR_variant | 3/3 | ENST00000335295.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBB | ENST00000335295.4 | c.*132C>A | 3_prime_UTR_variant | 3/3 | 1 | NM_000518.5 | P1 | ||
HBB | ENST00000647020.1 | c.*132C>A | 3_prime_UTR_variant | 3/3 | P1 | ||||
ENST00000644706.1 | upstream_gene_variant | ||||||||
HBB | ENST00000633227.1 | downstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152170Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000573 AC: 4AN: 698364Hom.: 0 Cov.: 9 AF XY: 0.00000804 AC XY: 3AN XY: 373098
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 24, 2022 | Variant summary: HBB c.*132C>A is located in the untranslated mRNA region downstream of the termination codon. The variant lies about 20 nucleotides downstream to the known polyA-tail signal, and thus it would likely not interfere with cleavage of the transcript and addition of polyA tail, however it can still affect potential protein binding sites or miRNA target sites that may influence transcript expression levels. The variant allele was found at a frequency of 7.3e-05 in 150942 control chromosomes, predominantly within the Latino subpopulation at a frequency of 0.00065 in the gnomAD database (v3.1 genomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.*132C>A, has been reported in the literature in two compound heterozygous Hispanic individuals, who were affected with Beta Thalassemia Intermedia, and carried a beta-0 variant in trans (Heath_2001, Rizo-de-la-Torre_2020), however, one of these individuals also carried the variant c.*129T>C in cis with the c.*132C>A variant (Heath_2001). These data do not allow clear conclusions about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, another variant affecting the same nucleotide, c.*132C>T, has also been reported in individuals affected with Beta Thalassemia Intermedia (PMIDs: 22862814, 31930713), suggesting that variants affecting this 3' UTR region might have functional effect. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
alpha Thalassemia;C0002895:Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:Methemoglobinemia, beta-globin type;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6;CN322236:Beta-thalassemia HBB/LCRB Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 18, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 23, 2023 | The c.*132C>A variant is located in the 3 prime untranslated region (UTR) of the HBB gene. It has been identified in individuals with beta thalassemia intermedia in trans with the known HBB c.118C>T pathogenic variant (PMIDs: 11279660 (2001) and 32142096 (2020)) and in cis with the HBB c.*129T>C variant (PMID: 11279660 (2001)).Taking into account the available information, we are unable to determine the clinical significance of this variant. Previous names for this variant include Nt494+132C>A. - |
Computational scores
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BayesDel_noAF
Benign
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Benign
Dann
Benign
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at