chr11-5227127-C-G
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The ENST00000647020.1(HBB):c.-106G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000307 in 812,098 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 0.00033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00030 ( 0 hom. )
Consequence
HBB
ENST00000647020.1 5_prime_UTR
ENST00000647020.1 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.48
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=-0.67).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|
Ensembl
Frequencies
GnomAD3 genomes 0.000335 AC: 51AN: 152192Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.000300 AC: 198AN: 659788Hom.: 0 Cov.: 8 AF XY: 0.000286 AC XY: 101AN XY: 353240
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GnomAD4 genome 0.000335 AC: 51AN: 152310Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24AN XY: 74476
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:4
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 22, 2024 | Observed in apparent homozygous state in a patient with moderate microcytic anemia in the literature (PMID: 25754248); Also known as -56C>G; This variant is associated with the following publications: (PMID: 35615994, 29157184, 18081706, 25754248) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 18, 2020 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 17, 2024 | The HBB c.-106G>C variant has been reported in the published literature in individuals with mild beta-thalassemia in the homozygous state or compound heterozygous state with the HBB c.92+1G>A beta(0)-thalassemia mutation (PMID: 18081706 (2008), 25754248 (2015)). More recent studies have characterized the variant as a benign variant or a silent mutation. It was observed in multiple heterozygous carriers with normal/borderline red cell indices and morphology, and compound heterozygosity with other globin mutations did not affect or worsen the phenotype (PMID: 29157184 (2017), 35615994 (2022)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect HBB mRNA splicing. Based on the available information, we are unable to determine the clinical significance of this variant. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 26, 2024 | The HBB c.-106G>C variant (rs63750681, HbVar ID: 2601, ClinVar Variation ID: 36281), also known as -56 (G>C), has been reported with a pathogenic beta globin variant in a patient with beta thalassemia intermedia (Agouti 2008) and in a patient with beta thalassemia minor (Belmokhtar 2022). Although the study suggested that the two variants are in-trans, parental samples were not available to confirm phase (Agouti 2008, Belmokhtar 2022). The c.-106G>C variant has also been reported homozygous in an individual presenting with minor B+-thalassemia with moderate microcytic anemia and low mean corpuscular hemoglobin concentration (Douzi 2015). More recently, the c.-106G>C variant was described in 10 individuals, eight heterozygotes with normal hematological and electrophoretic values, one individual who also carried Hb S with an indistinguishable phenotype from just Hb S carriers, and one individual compound heterozygous with a beta(0) variant and anti3.7 alpha globin rearrangement (Vinciguerra 2018). The authors concluded that the c.-106G>C variant is a rare benign variant (Vinciguerra 2018). This variant is found in the general population with a low overall allele frequency of 0.04% (11/31394 alleles) in the Genome Aggregation Database (v2.1.1). The variant is located in a weakly conserved nucleotide in the promoter region of beta globin that has not been previously associated with a molecular function, but a potential mild impact could not be excluded. Based on available information, the clinical significance of this variant is uncertain at this time. REFERENCES HbVar Database: https://globin.bx.psu.edu/hbvar/menu.html Agouti I et al. Beta-thalassemia intermedia due to two novel mutations in the promoter region of the beta-globin gene. Eur J Haematol. 2008 Apr;80(4):346-50. PMID: 18081706. Belmokhtar I et al. Molecular heterogeneity of ß-thalassemia variants in the Eastern region of Morocco. Mol Genet Genomic Med. 2022 Aug;10(8):e1970. PMID: 35615994. Douzi K et al. Two new beta+ -thalassemia mutation (B -56 (G ? C); HBBc. -106 G ? C) and (B -83 (G ? A); HBBc. -133 G ? A) described among the Tunisian population. Am J Hum Biol. 2015 Sep-Oct;27(5):716-9. PMID: 25754248. Vinciguerra M et al. Co-inheritance of HBB:c.-106G > C, a rare single nucleotide variation at position -56 relative to transcription initiation site, with other known mutations in the globin clusters. Hematology. 2018 Jul;23(6):368-372. PMID: 29157184 - |
beta Thalassemia Pathogenic:1Uncertain:1
| Pathogenic, no assertion criteria provided | curation | The ITHANET community portal, The Cyprus Institute of Neurology and Genetics | Nov 25, 2019 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 23, 2021 | - - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 30, 2024 | Variant summary: HBB c.-106G>C is located in the untranscribed region upstream of the HBB gene region. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00031 in 812098 control chromosomes (gnomAD database v4). This frequency is not significantly higher than estimated for a pathogenic variant in HBB causing Beta Thalassemia Intermedia (0.00031 vs 0.011), allowing no conclusion about variant significance. c.-106G>C, has been reported in the literature in a compound heterozygous patient together with a beta thalassemia major disease variant (c.92+1G>A), who had a beta thalassemia intermedia phenotype (Agouti_2008). The variant was also found in a homozygous individual, who displayed some features resembling to beta thalassemia minor, i.e. mild microcytic anemia, with low mean corpuscular hemoglobin concentration (Douzi_2015). These reports suggest that the variant might cause a milder phenotype, possibly affecting the beta gene expression. However, the variant was also reported in eight heterozygous individuals showing normal hematological values (i.e. being impossible to distinguish it from healthy, non-carrier subjects), and in at least three compound heterozygote patients carrying other globin disease variants, who showed phenotypes equivalent to patients carrying only the other alleles (Vinciguerra_2018, Belmokhtar_2022); therefore, these data suggest a benign role for the variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18081706, 25754248, 21423179, 27718361, 26076395, 29157184, 35615994). ClinVar contains an entry for this variant (Variation ID: 36281). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Beta-thalassemia HBB/LCRB Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
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 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 30, 2024 | - - |
Hb SS disease Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at