rs281865475
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000518.5(HBB):c.235del(p.Leu79TrpfsTer11) 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. L79L) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Consequence
HBB
NM_000518.5 frameshift
NM_000518.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.850
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 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 173 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-5226656-AG-A is Pathogenic according to our data. Variant chr11-5226656-AG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 632846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5226656-AG-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBB | NM_000518.5 | c.235del | p.Leu79TrpfsTer11 | frameshift_variant | 2/3 | ENST00000335295.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBB | ENST00000335295.4 | c.235del | p.Leu79TrpfsTer11 | frameshift_variant | 2/3 | 1 | NM_000518.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 36
GnomAD4 exome
Cov.:
36
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 17, 2019 | The Cd77/78 (-C) variant (HBB c.235delC; p.Leu79fs variant, also known as Leu78fs when numbered from the mature protein, rs281865475) is reported in the literature in the heterozygous state in individuals affected with beta-thalassemia minor (see link to HbVar and references therein). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be likely pathogenic. References: Link to HbVar for Cd77/78 (-C): http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=2533&.cgifields=histD - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 14, 2021 | The c.235del (p.Leu79Trpfs*11) pathogenic variant is a frameshift mutation that causes the premature termination of beta globin protein synthesis, and has been found among individuals with beta-thalassemia hematological features when in heterozygosity (PMID: 15481896 (2004)). - |
Beta-plus-thalassemia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2004 | - - |
Computational scores
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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