rs34533941
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000518.5(HBB):c.282_283dupTG(p.Asp95ValfsTer65) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. D95D) has been classified as Likely benign.
Frequency
Consequence
NM_000518.5 frameshift
Scores
Clinical Significance
Conservation
Publications
- dominant beta-thalassemiaInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
- hemoglobin M diseaseInheritance: AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen
- beta thalassemiaInheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
- beta-thalassemia HBB/LCRBInheritance: AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
- sickle cell disease and related diseasesInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- erythrocytosis, familial, 6Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- Heinz body anemiaInheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- sickle cell diseaseInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
- hereditary persistence of fetal hemoglobin-beta-thalassemia syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- beta-thalassemia intermediaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- beta-thalassemia majorInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- delta-beta-thalassemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- hemoglobin C diseaseInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- hemoglobin C-beta-thalassemia syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- hemoglobin E diseaseInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- hemoglobin E-beta-thalassemia syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- hereditary persistence of fetal hemoglobin-sickle cell disease syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- sickle cell-beta-thalassemia disease syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- sickle cell-hemoglobin c disease syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- sickle cell-hemoglobin d disease syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- sickle cell-hemoglobin E disease syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 36
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Beta zero thalassemia Pathogenic:1
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Dominant beta-thalassemia Pathogenic:1
The heterozygous p.Asp95ValfsTer65 variant in HBB was identified by our study in one individual with beta-thalassemia. The p.Asp95ValfsTer65 variant in HBB has been previously reported in one individual with beta-thalassemia (PMID: 2291578). This variant has also been reported in ClinVar (Variation ID: 15428) and has been interpreted by OMIM as pathogenic. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 95 and leads to a premature termination codon 65 amino acids downstream. This termination codon occurs within the terminal 50 bases of the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Heterozygous loss of function of the HBB gene is an established disease mechanism in autosomal dominant beta-thalassemia. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant beta-thalassemia. ACMG/AMP Criteria applied: PVS1_Strong, PM2_Supporting, PS4_Supporting (Richards 2015). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at