rs33941849
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_000518.5(HBB):c.2T>G(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,946 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 start_lost
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.94e-7 AC: 1AN: 1441946Hom.: 0 Cov.: 26 AF XY: 0.00000139 AC XY: 1AN XY: 718728
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
beta Thalassemia Pathogenic:4
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Variant summary: HBB c.2T>G (p.Met1Arg) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Arginine is not a known alternative start codon for eukaryotes in nature; thus, translation would be predicted to start at the next Met in the HBB protein (which is at amino acid 56), causing a loss of translation of the normal N-terminus of the protein. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251128 control chromosomes (gnomAD). c.2T>G has been reported in the literature in multiple individuals affected with Beta Thalassemia (e.g. Lam_1990, Lee_2002, Su_2003). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. This codon is in a mutational hotspot where other changes [such as: p.M1I (c.3G>A, C, and T), p.M1L, p.M1K, p.M1T and p.M1V] at the same residue have also been found in HBB patients (source: HGMD). Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:3
Disruption of the initiator codon has been observed in individual(s) with clinical features of autosomal recessive beta thalassemia (PMID: 12955718, 14715623, 29695942). This variant has been reported in individual(s) with autosomal dominant beta thalassemia (PMID: 8144357); however, the role of the variant in this condition is currently unclear. This variant is also known as CD0T>G, Initiation codon ATG‚ÜíAGG. ClinVar contains an entry for this variant (Variation ID: 15434). This variant disrupts a region of the HBB protein in which other variant(s) (p.Glu7Lys) have been determined to be pathogenic (PMID: 20301551, 23297836, 26372199, 27117572). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the HBB mRNA. The next in-frame methionine is located at codon 56. -
The HBB c.2T>G; p.Met1? variant (rs33941849, HbVar ID: 777) is reported in the literature in individuals affected with beta(0) thalassemia, with no detectable expression of the beta globin protein in a patient possessing a beta(0) thalassemia variant on the other chromosome (HbVar database and references therein). This variant is reported in ClinVar (Variation ID: 15434), and is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant ablates the canonical translation initiation codon, and is predicted to lead to an aberrant or absent 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 -
This variant disrupts in the translation initiation codon of the HBB mRNA and is predicted to interfere with HBB protein synthesis. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant is associated with beta-zero-thalassemia and is known to be a common Chinese beta-thalassemia pathogenic variant (PMID: 2306523 (1990), 27829298 (2016), 34474730 (2021), 34293487 (2021)). Based on the available information, this variant is classified as pathogenic. -
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