rs33915217
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000518.5(HBB):c.92+5G>T variant causes a splice donor 5th base, 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 Pathogenic (★★).
Frequency
Consequence
NM_000518.5 splice_donor_5th_base, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HBB | NM_000518.5 | c.92+5G>T | splice_donor_5th_base_variant, intron_variant | ENST00000335295.4 | NP_000509.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HBB | ENST00000335295.4 | c.92+5G>T | splice_donor_5th_base_variant, intron_variant | 1 | NM_000518.5 | ENSP00000333994 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251204Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135754
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1459918Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 726420
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 06, 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. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs33915217, gnomAD 0.0009%). This variant has been observed in individuals with beta-thalassemia (PMID: 2439149). ClinVar contains an entry for this variant (Variation ID: 15448). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in alternate splicing and introduces a premature termination codon (PMID: 2439149). The resulting mRNA is expected to undergo nonsense-mediated decay. 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: 2200760, 3021139, 23162295, 27263053). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 17, 2023 | The HBB c.92+5G>T variant (rs33915217, HbVar ID: 825), also known as IVS-I-5 (G->T), has been reported in the homozygous or compound heterozygous state in several individuals affected with beta(+) thalassemia (Atweh 1987, HbVar database and references therein). Functional studies indicate that the variant causes aberrant splicing of the HBB transcript and reduction of full-length mRNA (Atweh 1987). The variant is listed as pathogenic in ClinVar (Variation ID: 15448), and observed once in the Genome Aggregation Database (1/251204 alleles). Consistent with functional studies, computational analyses (Alamut v.2.11) predict that this variant impacts splicing by weakening the nearby canonical donor splice site. Based on available information, the variant c.92+5G>T is classified as pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Atweh G et al. A new mutation in IVS-1 of the human beta globin gene causing beta thalassemia due to abnormal splicing. Blood. 1987; 70(1):147-51. PMID: 2439149. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 26, 2023 | Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23348723, 22975760, 25525159, 9163586, 2577233, 2439149, 33092414) - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 07, 2016 | - - |
beta Thalassemia Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Sep 03, 2015 | - - |
Pathogenic, no assertion criteria provided | curation | The ITHANET community portal, The Cyprus Institute of Neurology and Genetics | Nov 25, 2019 | - - |
Beta-thalassemia major Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing;curation | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2011 | - - |
Beta-plus-thalassemia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 1989 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at