rs33971634
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000518.5(HBB):c.382C>T(p.Gln128Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,252 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
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Consequence
HBB
NM_000518.5 stop_gained
NM_000518.5 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 9.01
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 exon, not predicted to undergo nonsense mediated mRNA decay. There are 54 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-5225660-G-A is Pathogenic according to our data. Variant chr11-5225660-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1705074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5225660-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBB | NM_000518.5 | c.382C>T | p.Gln128Ter | stop_gained | 3/3 | ENST00000335295.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBB | ENST00000335295.4 | c.382C>T | p.Gln128Ter | stop_gained | 3/3 | 1 | NM_000518.5 | P1 | |
HBB | ENST00000647020.1 | c.382C>T | p.Gln128Ter | stop_gained | 3/3 | P1 | |||
HBB | ENST00000475226.1 | n.314C>T | non_coding_transcript_exon_variant | 2/2 | 2 | ||||
HBB | ENST00000633227.1 | c.*198C>T | 3_prime_UTR_variant, NMD_transcript_variant | 3/3 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152134Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251276Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135810
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GnomAD4 exome Cov.: 31
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152252Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74448
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Dominant beta-thalassemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 17, 2023 | Variant summary: HBB c.382C>T (p.Gln128X, also reported as p.Glu127X) is located in exon 3 (i.e. in the last exon) of the HBB gene. The current variant results in a premature termination codon that is not expected to cause nonsense mediated decay (NMD), but is predicted to cause a C-terminal truncation, removing a part of the 147 amino acid long protein. A truncation downstream of this position has been classified as pathogenic for dominant B-THAL by our laboratory. The variant allele was found at a frequency of 4e-06 in 251276 control chromosomes (gnomAD). c.382C>T has been reported in the literature in multiple individuals affected with considerable variation in phenotype (even within the same famlily), ranging from mild, clinically asymptomatic anemia to severe hemolytic anemia with splenomegaly (e.g. Hall_1991, Van Weel_1999, Prehu_2005), where occasionally the presence of Heinz bodies was also noted. These data indicate that the variant is likely associated with disease. A publication reported experimental evidence and demonstrated that substantial amounts of mutant beta-mRNA were present in individuals carrying the variant, thus demonstrating that the variant does not result in nonsense mediated decay (NMD), suggesting that a truncated protein product can be produced, which might also explain the presence of the occasionally reported Heinz bodies (Hall_1994). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic for dominant B-THAL. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 14, 2023 | The HBB c.382C>T (p.Gln128*) variant creates a premature stop codon in the last exon of the beta-globin gene. An RNA study indicates the mutant mRNA transcript is not degraded by nonsense-mediated decay, and is predicted to result in the production of a truncated protein lacking the terminal 20 amino acids of the beta-globin chain (PMID: 8161774 (1994)). This variant is associated with dominant beta-thalassemia in which heterozygous carriers present with varying phenotype, ranging from clinically asymptomatic anemia to thalassemia intermedia (PMIDs: 9450794 (1998), 8161774 (1994), 1958498 (1991)). In addition, this variant has been reported as a de novo variant in a heterozygous individual with microcytic hypochromic hemolytic anemia and splenomegaly (PMID: 10569730 (1999)). Previous names for this variant include Codon 127 C>T. Based on the available information, this variant is classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D
Vest4
GERP RS
Splicing
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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