rs33914668
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000335295.4(HBB):c.316-2A>G variant causes a splice acceptor change. The variant allele was found at a frequency of 0.000013 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
HBB
ENST00000335295.4 splice_acceptor
ENST00000335295.4 splice_acceptor
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 5.51
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 Pathogenic. Variant got 18 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-5225728-T-C is Pathogenic according to our data. Variant chr11-5225728-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 21191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5225728-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HBB | NM_000518.5 | c.316-2A>G | splice_acceptor_variant | ENST00000335295.4 | NP_000509.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HBB | ENST00000335295.4 | c.316-2A>G | splice_acceptor_variant | 1 | NM_000518.5 | ENSP00000333994 | P1 | |||
HBB | ENST00000647020.1 | c.316-2A>G | splice_acceptor_variant | ENSP00000494175 | P1 | |||||
HBB | ENST00000633227.1 | c.*132-2A>G | splice_acceptor_variant, NMD_transcript_variant | 3 | ENSP00000488004 | |||||
HBB | ENST00000475226.1 | n.248-2A>G | splice_acceptor_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 152090Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251048Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135686
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461706Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727164
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152208Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6AN XY: 74404
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:12Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
beta Thalassemia Pathogenic:4Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 09, 2019 | NM_000518.4(HBB):c.316-2A>G is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy; it is associated with beta thalassemia and is classified as a beta-zero variant. Sources cited for classification include the following: PMID 21250876, 2987809 and 2123063. Classification of NM_000518.4(HBB):c.316-2A>G is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, no assertion criteria provided | curation | The ITHANET community portal, The Cyprus Institute of Neurology and Genetics | Nov 25, 2019 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 18, 2018 | Variant summary: HBB c.316-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 3 acceptor site. Two publications report experimental evidence that this variant affects mRNA splicing (Antonarakis_1984, Atweh_1985). The variant allele was found at a frequency of 1.1e-05 in 276762 control chromosomes (gnomAD). The variant, c.316-2A>G, has been reported in the literature in multiple individuals affected with Beta Thalassemia (Bravo-Urquiola_2012, Codrington_1990, Antonarakis_1984, Atweh_1985, Huisman_1997). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 27, 2023 | The HBB c.316-2A>G variant (also known as IVS-II-849 (A->G), rs33914668, Hbvar ID: 940) is reported in the literature in both homozygous and compound heterozygous individuals affected with beta(0) thalassemia (Antonarakis 1984, Atweh 1985, HbVar database and references therein). This variant is found on only three chromosomes (3/282432 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant abolishes the canonical splice acceptor site of intron 2, which is likely to disrupt gene function. Indeed, RNA analyses of patient cells carrying the c.316-2A>G variant suggest altered splicing and retention of sections of intron 3 in the mature mRNA (Antonarakis 1984, Atweh 1985). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Antonarakis S et al. beta-Thalassemia in American Blacks: novel mutations in the "TATA" box and an acceptor splice site. Proc Natl Acad Sci U S A. 1984; 81(4):1154-8. PMID: 6583702 Atweh G et al. Beta-thalassemia resulting from a single nucleotide substitution in an acceptor splice site. Nucleic Acids Res. 1985; 13(3):777-90. PMID: 2987809 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 02, 2024 | Canonical splice site variant expected to result in aberrant splicing, and published functional studies show this variant causes the production of an alternatively splice transcript which is not able to encode normal beta-globin (PMID: 6583702); This variant is associated with the following publications: (PMID: 21250876, 22563936, 22975760, 9342003, 32172616, 6583702, 1427786, 2123063, 2987809, 30626236, 23348723, 27251090, 26583619, 38293657, 37496383, 33935034, 38007159, 36106931) - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 30, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 18, 2023 | This sequence change affects an acceptor splice site in intron 2 of the HBB gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the gain of 90 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs33914668, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with autosomal recessive beta-thalassemia (PMID: 2123063, 6583702). It has also been observed to segregate with disease in related individuals. This variant is also known as IVSII-849A>G. ClinVar contains an entry for this variant (Variation ID: 21191). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in intron 2 (PMID: 6583702). For these reasons, this variant has been classified as Pathogenic. - |
Beta zero thalassemia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 1992 | - - |
alpha Thalassemia;C0002895: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 | Feb 25, 2022 | - - |
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 | Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili | Nov 07, 2023 | - - |
Hb SS disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at