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

Genomes: not found (cov: 32)

Consequence

HBB
NM_000518.5 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 1.30

Publications

0 publications found
Variant links:
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]
HBB Gene-Disease associations (from GenCC):
  • dominant beta-thalassemia
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
  • hemoglobin M disease
    Inheritance: AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen
  • beta thalassemia
    Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
  • beta-thalassemia HBB/LCRB
    Inheritance: AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
  • sickle cell disease and related diseases
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • erythrocytosis, familial, 6
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
  • Heinz body anemia
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • sickle cell disease
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
  • hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • beta-thalassemia intermedia
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • beta-thalassemia major
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • delta-beta-thalassemia
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • hemoglobin C disease
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • hemoglobin C-beta-thalassemia syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • hemoglobin E disease
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • hemoglobin E-beta-thalassemia syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • sickle cell-beta-thalassemia disease syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • sickle cell-hemoglobin c disease syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • sickle cell-hemoglobin d disease syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • sickle cell-hemoglobin E disease syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 97 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-5226608-T-TCA is Pathogenic according to our data. Variant chr11-5226608-T-TCA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15428.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HBBNM_000518.5 linkc.282_283dupTG p.Asp95ValfsTer65 frameshift_variant Exon 2 of 3 ENST00000335295.4 NP_000509.1 P68871D9YZU5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HBBENST00000335295.4 linkc.282_283dupTG p.Asp95ValfsTer65 frameshift_variant Exon 2 of 3 1 NM_000518.5 ENSP00000333994.3 P68871

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
36
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Beta zero thalassemia Pathogenic:1
Jan 01, 1990
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Dominant beta-thalassemia Pathogenic:1
Jan 25, 2023
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:curation

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
1.3
Mutation Taster
=2/198
disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs34533941; hg19: chr11-5247838; API