11-5226925-C-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000518.5(HBB):c.92+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000518.5 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251204Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135754
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1459918Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 726420
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
beta Thalassemia Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
Pathogenic, no assertion criteria provided | curation | The ITHANET community portal, The Cyprus Institute of Neurology and Genetics | Nov 25, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing;curation | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2011 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Aug 06, 2014 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 19, 2023 | The HBB c.92+5G>A variant (rs33915217, HbVar ID: 822), also known as IVS-I-5 (G->A), is reported in the literature in multiple individuals affected with severe beta(+) thalassemia (Lapoumeroulie 1987, Muniz 2000, Perea 2004, HbVar database and references therein). This variant is listed in ClinVar (Variation ID: 15449), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Functional studies indicate that the variant causes aberrant splicing of the HBB RNA, leading to reduced production of full-length transcripts (Lapoumeroulie 1987). Based on the above information, the variant is classified as pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Lapoumeroulie C et al. Expression of a beta thalassemia gene with abnormal splicing. Nucleic Acids Res. 1987 15(20):8195-204. PMID: 3671081. Muniz A et al. Beta-thalassaemia in Cubans: novel allele increases the genetic diversity at the HBB locus in the Caribbean. Am J Hematol. 2000 64(1):7-14. PMID: 10815781. Perea F et al. Molecular spectrum of beta-thalassemia in the Mexican population. Blood Cells Mol Dis. 2004 33(2):150-2. PMID: 15315794. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 24, 2023 | This sequence change falls in intron 1 of the HBB gene. It does not directly change the encoded amino acid sequence of the HBB protein. It affects a nucleotide within the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 15449). This variant is also known as IVS-1-5 (G>A) or IVS-I-5. This variant has been observed in individuals with beta thalassemia (PMID: 1917531, 2200760, 3021139, 23590658, 28366028; 10815781.). This variant is present in population databases (rs33915217, gnomAD 0.0009%). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.92+5G nucleotide in the HBB gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 6188062, 18294253, 19000664, 22392582, 23162295, 27263053). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 3671081). - |
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 | Apr 25, 2024 | - - |
Beta-plus-thalassemia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 14, 1986 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at