rs63750223
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_000518.5(HBB):c.93-21_96del variant causes a splice acceptor, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
HBB
NM_000518.5 splice_acceptor, coding_sequence, intron
NM_000518.5 splice_acceptor, coding_sequence, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.47
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.5 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.6, offset of -18, new splice context is: gactcttgggtttctgatAGgca. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-5226795-GCAGCCTAAGGGTGGGAAAATAGACC-G is Pathogenic according to our data. Variant chr11-5226795-GCAGCCTAAGGGTGGGAAAATAGACC-G is described in ClinVar as [Pathogenic]. Clinvar id is 632854.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-5226795-GCAGCCTAAGGGTGGGAAAATAGACC-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBB | NM_000518.5 | c.93-21_96del | splice_acceptor_variant, coding_sequence_variant, intron_variant | 2/3 | ENST00000335295.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBB | ENST00000335295.4 | c.93-21_96del | splice_acceptor_variant, coding_sequence_variant, intron_variant | 2/3 | 1 | NM_000518.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
beta Thalassemia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 25, 2019 | Variant summary: HBB c.93-21_96del25 is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: five predict the variant abolishes a 3 prime acceptor site. A slightly different variant affecting the same region (c.93-22_95del25) was confirmed by a functional study to affect splicing (Orkin_1983), providing supporting evidence for a pathogenic role of c.93-21_96del25. This variant was absent in 251348 control chromosomes (gnomAD). c.93-21_96del25 has been reported in the literature in individuals affected with Beta Thalassemia (Hassan_2014, Aldakeel_2019). These data indicate that the variant may be associated with disease. No other 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. - |
Pathogenic, no assertion criteria provided | curation | The ITHANET community portal, The Cyprus Institute of Neurology and Genetics | Nov 25, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at