rs63751208
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The ENST00000647020.1(HBB):c.-151C>T 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 0.0000957 in 689,530 control chromosomes in the GnomAD database, including 1 homozygotes. 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
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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HBB | ENST00000647020.1 | c.-151C>T | 5_prime_UTR_premature_start_codon_gain_variant | Exon 1 of 3 | ENSP00000494175.1 | |||||
HBB | ENST00000647020.1 | c.-151C>T | 5_prime_UTR_variant | Exon 1 of 3 | ENSP00000494175.1 | |||||
HBB | ENST00000380315.2 | c.-18-133C>T | intron_variant | Intron 2 of 3 | 5 | ENSP00000369671.2 |
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152190Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.000104 AC: 56AN: 537340Hom.: 1 Cov.: 4 AF XY: 0.000124 AC XY: 36AN XY: 290572
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152190Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74352
ClinVar
Submissions by phenotype
beta Thalassemia Pathogenic:5Other:1
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Variant summary: c.-151C>T affects a non-conserved nucleotide in the promoter of HBB gene. Mutation Taster predicts a damaging outcome for this variant. This prediction was confirmed by a CAT promoter activity assay showing that this variant decreased promoter activity by 70% (Gonzalez-Redondo_1989). This variant was found in 1/31016 control chromosomes at a frequency of 0.0000322, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). This variant is a well-known pathogenic HBB variant and has been reported in more than thirty unrelated patients with b-thalassemia intermedia. In addition, multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic. -
The c.-151C>T variant in HBB, also known as -101C>T, has been reported in the compound heterozygous state with a severe beta thalassemia variant in numerous individuals with a mild form of thalassemia intermedia. It is the most common silent beta-thalassemia variant among individuals of Mediterranean descent (Gonzalez-Redondo 1989 PMID: 2713503, Ristaldi 1990 PMID: 2346726, Rund 1997 PMID: 8980256, HbVar, Maragoudaki 1999 PMID: 10606872). It has also been reported in ClinVar (Variation ID 15461) and has been identified in 10/68034 European chromosomes by gnomAD (https://gnomad.broadinstitute.org/). This variant occurs in the beta-globin promoter, and in vitro functional studies support an impact on promoter activity (Gonzalez-Redondo 1989 PMID: 2713503). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive beta thalassemia. ACMG/AMP Criteria applied: PM2_Supporting, PS4, PM1. -
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not provided Pathogenic:5
Published functional studies demonstrate a significant loss of function (Gonzalez-Redondo et al., 1989); Not observed at significant frequency in large population cohorts (gnomAD); Reported as the most common silent beta-thalassemia variant among individuals of Mediterranean background (Maragoudaki et al., 1999); This variant is associated with the following publications: (PMID: 2001456, 7683931, 2346726, 25910213, 2713503, 7909640, 26202972, 28385923, 31395865, 34426522, 10606872) -
The HBB c.-151C>T variant (rs63751208, HbVar ID: 649), also known as -101C>T, is associated with silent beta thalassemia in heterozygous carriers and has been described in individuals with a mild form of thalassemia intermedia who were compound heterozygous with a severe beta thalassemia variant (Gonzalez-Redondo 1989, Ristaldi 1990, Rund 1997, see HbVar and references therein). This variant is also reported in ClinVar (Variation ID: 15461). It is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant is located in a conserved region of the beta globin gene promoter and is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Gonzalez-Redondo JM et al. A C----T substitution at nt--101 in a conserved DNA sequence of the promotor region of the beta-globin gene is associated with "silent" beta-thalassemia. Blood. 1989 May 1;73(6):1705-11. PMID: 2713503 Ristaldi MS et al. The C-T substitution in the distal CACCC box of the beta-globin gene promoter is a common cause of silent beta thalassaemia in the Italian population. Br J Haematol. 1990 Apr;74(4):480-6. PMID: 2346726 Rund D et al. Genetic analysis of beta-thalassemia intermedia in Israel: diversity of mechanisms and unpredictability of phenotype. Am J Hematol. 1997 Jan;54(1):16-22. PMID: 8980256 -
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The HBB c.-151C>T variant (also known as -101C>T) has been reported in the homozygous and compound heterozygous state in individuals with beta-thalassemia intermedia (PMID: 30820323 (2019), 10606872 (1999), 2346726 (1990)). A functional study indicate this variant results in reduced HBB promoter activity (PMID: 2713503 (1989)). The frequency of this variant in the general population, 0.000032 (1/31400 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as pathogenic. -
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 (rs63751208, gnomAD 0.007%). This variant has been observed in individuals with HBB-related conditions, usually co-occurring with another severe beta-thalassemia variant (PMID: 2001456, 2713503, 10606872). It has also been observed to segregate with disease in related individuals. Of note, one homozygous individual was reported with beta-thalassemia intermedia (PMID: 30820323). This variant is also known as -101C>T. Studies have shown that this variant alters HBB gene expression (PMID: 2713503). For these reasons, this variant has been classified as Pathogenic. -
Beta-thalassemia HBB/LCRB Pathogenic:1
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HBB-related disorder Pathogenic:1
The HBB c.-151C>T variant is located in the 5' untranslated region. This variant, also referred to as c.-101C>T using legacy nomenclature, is predicted to disrupt the CACCC promoter motif and has been reported to be causative for Beta-Thalassemia in the presence of a second pathogenic allele (Gonzalez-Redondo et al. 1989. PubMed ID: 2713503; Rund et al. 1997. PubMed ID: 8980256; Ristaldi et al. 1999. PubMed ID: 10575515). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted 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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Beta-plus-thalassemia Pathogenic:1
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Malaria, susceptibility to Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at