11-5227158-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The ENST00000647020.1(HBB):c.-137C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 706,420 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 Likely pathogenic (★★).
Frequency
Consequence
ENST00000647020.1 5_prime_UTR
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000902 AC: 5AN: 554166Hom.: 0 Cov.: 5 AF XY: 0.0000100 AC XY: 3AN XY: 299838
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152254Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74452
ClinVar
Submissions by phenotype
not provided Pathogenic:3
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 not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with autosomal recessive beta-thalassemia (PMID: 2018842, 20524821, 27821015). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as -87C>T. ClinVar contains an entry for this variant (Variation ID: 36287). Studies have shown that this variant alters HBB gene expression (PMID: 2018842). For these reasons, this variant has been classified as Pathogenic. -
Published functional studies demonstrate a damaging effect, as transfection of the gene with c.-137C>T in HeLa cells showed a reduction of beta globin gene transcriptional activity (Kulozik et al., 1991; Kircher et al., 2019); Also known as -87C>T; No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 11857746, 2018842, 20524821, 31395865, 27821015, 9163586, 21119755, 21423179, 1550780) -
The HBB c.-137C>T variant (rs33941377, HbVarID: 759), also known as -87C>T, is reported in the literature in several individuals with beta thalassemia intermedia, both of whom carried an additional pathogenic variant (Kulozik 1991, Gallagher 2016, HbVar database). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant is located in HBB promoter in the CACCC box that promotes gene transcription, and functional assays indicate that this variant results in reduced transcriptional activity (Kulozik 1991). Based on available information, this variant is considered pathogenic. References: Link to HbVar: https://globin.bx.psu.edu/hbvar/menu.html Gallagher PG et al. Mutation in a Highly Conserved COOH-Terminal Residue of Kruppel-Like Factor 1 Associated with Elevated Hb F in a Compound Heterozygous beta-Thalassemia Patient with a Nontransfusion-Dependent Thalassemia Phenotype. Hemoglobin. 2016 Sep;40(5):361-364. PMID: 27821015. Kulozik AE et al. Thalassemia intermedia: moderate reduction of beta globin gene transcriptional activity by a novel mutation of the proximal CACCC promoter element. Blood. 1991 May 1;77(9):2054-8. PMID: 2018842. -
Beta thalassemia intermedia Pathogenic:1
Variant summary: HBB c.-137C>T is located in the untranscribed region upstream of the HBB gene region. The variant was absent in 31398 control chromosomes. Ithanet lists this variant in association with + phenotype with relative carrier frequencies as follow: Czech Republic 2%, Slovakia 2%, Germany 1%, United Kingdom 0.2%, Italy 0.1%, and India 0.04%. The variant was found in multiple patients with symptoms ranging from beta-thalassemia major to beta-thalassemia intermedia depending on the second variant in trans and/or presence of alteration in genes encoding a-chain. Functional studies have shown that this variant leads to reduced transcription rate and synthesis of HBB (Kulozik_1991). The following publications have been ascertained in the context of this evaluation (PMID: 2018842, 11857746, 21119755, 21423179, 20524821, 27821015, 1550780). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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 Thalassemia Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at