rs63750783
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000518.5(HBB):c.47G>A(p.Trp16*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000518.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152208Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000876 AC: 22AN: 251244Hom.: 0 AF XY: 0.0000958 AC XY: 13AN XY: 135770
GnomAD4 exome AF: 0.0000328 AC: 48AN: 1461398Hom.: 0 Cov.: 33 AF XY: 0.0000413 AC XY: 30AN XY: 727030
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152326Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74500
ClinVar
Submissions by phenotype
beta Thalassemia Pathogenic:6
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The p.Trp16X variant (also known as Trp15X) has been reported in numerous individuals with beta thalassemia (selected references Kazazian 1984 PMID: 6714226, HbVar database: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=791 ). It has been reported in ClinVar (Variation ID 15403) and was identified in 4/4834 South Asian chromosomes by gnomAD (https://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 16, which is predicted to lead to a truncated or absent protein. Loss of function of the HBB gene is an established disease mechanism in autosomal recessive beta thalassemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive beta thalassemia. ACMG/AMP Criteria applied: PM2_Supporting, PVS1, PM3_Strong. -
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Variant summary: The HBB c.47G>A (p.Trp16X) 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. Variant c.48G>A that gives the same codon change has been classified as pathogenic by our laboratory. One in silico tool predicts a damaging outcome for this variant. This variant was found in 14/121364 control chromosomes at a frequency of 0.0001154, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). This variant has been reported in numerous beta thalassemia patients and is considered as a common disease variant. In addition, multiple reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
NM_000518.4(HBB):c.47G>A(W16*) is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy and is associated with beta thalassemia. Sources cited for classification include the following: PMID 21389146, 15278762, 18294253 and 21389146. Classification of NM_000518.4(HBB):c.47G>A(W16*) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
not provided Pathogenic:6
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The HBB c.47G>A; p.Trp16Ter variant (also known as Trp15Ter when numbered from the mature protein or as Codon 15 (G->A); TGG->TAG, rs63750783, HbVar ID: 791) has been reported in individuals with beta(0) thalassemia (Kazazian 1984, HbVar database and references therein). This variant is found in the general population with an overall allele frequency of 0.009% (22/251244 alleles) in the Genome Aggregation Database. This variant introduces a premature termination codon, but the mRNA is resistant to nonsense-mediated decay (Neu-Yilik 2011); thus it is predicted to result in a truncated protein. Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Kazazian HH Jr et al. Molecular characterization of seven beta-thalassemia mutations in Asian Indians. EMBO J. 1984; 3(3):593-6. PMID: 6714226. Neu-Yilik G et al. Mechanism of escape from nonsense-mediated mRNA decay of human beta-globin transcripts with nonsense mutations in the first exon. RNA. 2011; 17(5):843-54. PMID: 21389146. -
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Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22975760, 30200837, 29669226, 7668221, 6714226, 28635337, 21389146, 8091935, 27263053) -
This sequence change creates a premature translational stop signal (p.Trp16*) in the HBB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 132 amino acid(s) of the HBB protein. This variant is present in population databases (rs63750783, gnomAD 0.06%). This premature translational stop signal has been observed in individuals with beta thalassemia and has been reported as a prevalent disease-associated variant in several populations (PMID: 1581247, 6714226, 7668221, 18294253, 20395516, 27263053, 27828729). This variant is also known as "Codon 15 (TGG->TGA)". ClinVar contains an entry for this variant (Variation ID: 15403). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Beta-thalassemia HBB/LCRB Pathogenic:2
The stop gain c.47G>A (p.Trp16Ter) variant in the HBB gene has been reported previously in both homozygous and compound heterozygous states in multiple individuals affected with beta-thalassemia and is also one of the most common HBB variants causing beta-thalassemia (Yasmeen et al. 2016; Panja et al. 2017). The p.Trp16Ter variant is reported with an allele frequency of 0.008% in the gnomAD exomes database. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic. As this variant in HBB gene is in heterozygous state, it is suggestive of Beta thalassemia trait. -
The HBB c.47G>A; p.Trp16Ter variant, it is a beta 0 type of mutation, The variant introduce a premature termination codon results into nonsense mediated decay of HBB mRNA. The frequency of this variant among thalassemia patient in Eastern India is 2.10 % as per our multicentric project - A Genetic Diagnostic Algorithm Based Study for Thalassemia in Northern and Eastern Indian Populations", Funded by Dept. of Biotechnology , Govt of India [Project No. BT/PR26461/MED/12/821/2018] -
Beta zero thalassemia Pathogenic:1
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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
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Hb SS disease Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at