rs33959855
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000518.5(HBB):c.67G>T(p.Glu23*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,554 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 Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461554Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727112
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
beta Thalassemia Pathogenic:2
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Variant summary: HBB c.67G>T (p.Glu23X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251278 control chromosomes. c.67G>T has been reported in the literature in individuals affected with Beta Thalassemia (e.g. Ghanem_1992). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 1301930). ClinVar contains an entry for this variant (Variation ID: 869359). Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:1
This sequence change creates a premature translational stop signal (p.Glu23*) 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 not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with beta-thalassemias (PMID: 1301930, 27756326). This variant is also known as a codon 22 nonsense mutation (GAA-TAA) or codon 22 G>T. ClinVar contains an entry for this variant (Variation ID: 869359). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at