rs33969853
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000518.5(HBB):c.217_218insA(p.Ser73LysfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
HBB
NM_000518.5 frameshift
NM_000518.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.303
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
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 185 pathogenic variants in the truncated region.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 11-5226674-C-CT is Pathogenic according to our data. Variant chr11-5226674-C-CT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBB | NM_000518.5 | c.217_218insA | p.Ser73LysfsTer2 | frameshift_variant | 2/3 | ENST00000335295.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBB | ENST00000335295.4 | c.217_218insA | p.Ser73LysfsTer2 | frameshift_variant | 2/3 | 1 | NM_000518.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251430Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135888
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461878Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1AN XY: 727244
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
beta Thalassemia Pathogenic:4
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 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 15, 2016 | Variant summary: The HBB c.217dupA (p.Ser73Lysfs) variant results in a premature termination codon, predicted to cause a truncated or absent HBB protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Gly84fs). One in silico tool predicts a damaging outcome for this variant. Additionally, Cheng_PNAS_1984 reported the absence of beta-globin RNA in erythroid cells of a patient homozygous for this variant. The variant was reported in multiple unrelated BTHAL patients in the literature, and authors all classified the variant as pathogenic. This variant was found in 1/121394 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). Taken together, this variant is classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 20, 2019 | NM_000518.4(HBB):c.217dupA(aka p.S73Kfs*2) is classified as likely pathogenic in the context of Hb beta chain-related hemoglobinopathy. Please note that S73Kfs*2 is associated with beta thalassemia and is classified as a beta-zero variant. Sources cited for classification include the following: PMID 6585831. Classification of NM_000518.4(HBB):c.217dupA(aka p.S73Kfs*2) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is observed in an individual with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 06, 2022 | The HBB c.217dupA; p.Ser73LysfsTer2 variant (also known as Ser72fs when numbered from the mature protein or as codon 71/72 (+A); HbVar ID: 869) has been reported in individuals with beta(0) thalassemia, including in a homozygous individual with no detectable HBB mRNA (see HbVar, Cheng 1984). This variant is found on only two chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the c.217dupA variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Cheng T et al. beta-Thalassemia in Chinese: use of in vivo RNA analysis and oligonucleotide hybridization in systematic characterization of molecular defects. Proc Natl Acad Sci U S A. 1984; 81(9):2821-5. PMID: 6585831. - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 30, 2020 | The HBB c.217dup (p.Ser73Lysfs*2) pathogenic variant alters the translational reading frame of the HBB mRNA and causes the premature termination of HBB protein synthesis. This variant has been reported to be associated with beta(0)-thalassemia (PMIDs: 26956563 (2016), 24369358 (2014), 6585831 (1984)). - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change creates a premature translational stop signal (p.Ser73Lysfs*2) in the HBB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309). This variant is present in population databases (rs606231217, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with autosomal recessive beta thalassemia (PMID: 6585831). This variant is also known as c.216_217insA or as an insertion of an A nucleotide between codons 71 and 72. ClinVar contains an entry for this variant (Variation ID: 15419). For these reasons, this variant has been classified as Pathogenic. - |
Beta zero thalassemia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 1984 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 02, 2016 | The c.217dupA pathogenic mutation (also known as codons 71/72 insertion A), located in coding exon 2 of the HBB gene, results from a duplication of A at nucleotide position 217, causing a translational frameshift with a predicted alternate stop codon (p.S73Kfs*2). This variant was identified previously in a homozygous individual with beta-thalassemia (Cheng TC et al. Proc. Natl. Acad. Sci. U.S.A., 1984 May;81:2821-5). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at