rs33986703
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000518.5(HBB):c.52A>T(p.Lys18Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000118 in 1,614,014 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 (★★). Synonymous variant affecting the same amino acid position (i.e. K18K) has been classified as Likely benign.
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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBB | NM_000518.5 | c.52A>T | p.Lys18Ter | stop_gained | 1/3 | ENST00000335295.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBB | ENST00000335295.4 | c.52A>T | p.Lys18Ter | stop_gained | 1/3 | 1 | NM_000518.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152212Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251268Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135792
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461684Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727164
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152330Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74502
ClinVar
Submissions by phenotype
not provided Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 28, 2022 | 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: 21389146, 88735, 26029792, 30275481, 34426522, 8161731, 2143120, 26715484, 22975760, 29669226, 29695942) - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 16, 2023 | The HBB c.52A>T; p.Lys18Ter variant (also known as Lys17Ter when numbered from the mature protein or as Codon 17 (A>T), rs33986703, HbVar ID: 800) has been reported in multiple individuals with beta thalassemia, and is considered a beta(0) thalassemia variant (HbVar database and references therein). This variant introduces a premature termination codon, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Link to HbVar: https://globin.bx.psu.edu/hbvar/hbvar.html - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Jul 13, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 01, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 30, 2021 | The nonsense variant causes the premature termination of HBB protein synthesis. In addition, it has been reported to be associated with beta(0)-thalassemia in the published literature (PMID: 29695942 (2018), 9101288 (1997), 2606476 (1989) and 88735 (1979)). Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | This sequence change creates a premature translational stop signal (p.Lys18*) 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 (rs33986703, gnomAD 0.06%). This premature translational stop signal has been observed in individuals with beta thalassemia (PMID: 88735, 24857915, 26029792). It is commonly reported in individuals of Asian ancestry (PMID: 20412082, 25089872, 25849334, 29695942). This variant is also known as "Codon 17 (A->T)" and "AAG(Lys)->TAG(stop codon) beta0". ClinVar contains an entry for this variant (Variation ID: 15401). 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 Pathogenic:5Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 28, 2016 | Variant summary: The HBB c.52A>T (p.Lys18X) 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.c.85dupC/p.Leu29fsX16). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/121842 control chromosomes at a frequency of 0.0000164, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). This variant has been reported in many BTHAL patients (mostly East Asian) both homozygously and in compound heterozygosity with other pathogenic variant. In addition, multiple reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
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 | Myriad Genetics, Inc. | Dec 19, 2019 | NM_000518.4(HBB):c.52A>T(K18*) 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 22335963. Classification of NM_000518.4(HBB):c.52A>T(K18*) 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 reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 24, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Beta zero thalassemia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2000 | - - |
Beta-thalassemia HBB/LCRB Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Mar 15, 2022 | - - |
alpha Thalassemia;C0002895:Hb SS disease;C0005283:beta Thalassemia;C0700299:Heinz body anemia;C1840779:METHEMOGLOBINEMIA, BETA TYPE;C1841621:Fetal hemoglobin quantitative trait locus 1;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Hb SS disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at