11-5225728-T-G
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000518.5(HBB):c.316-2A>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000124 in 1,613,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
HBB
NM_000518.5 splice_acceptor, intron
NM_000518.5 splice_acceptor, intron
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 5.51
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
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-5225728-T-G is Pathogenic according to our data. Variant chr11-5225728-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 21190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5225728-T-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HBB | ENST00000335295.4 | c.316-2A>C | splice_acceptor_variant, intron_variant | Intron 2 of 2 | 1 | NM_000518.5 | ENSP00000333994.3 | |||
HBB | ENST00000647020.1 | c.316-2A>C | splice_acceptor_variant, intron_variant | Intron 2 of 2 | ENSP00000494175.1 | |||||
HBB | ENST00000475226.1 | n.248-2A>C | splice_acceptor_variant, intron_variant | Intron 1 of 1 | 2 | |||||
HBB | ENST00000633227.1 | n.*132-2A>C | splice_acceptor_variant, intron_variant | Intron 2 of 2 | 3 | ENSP00000488004.1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152090Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461706Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727164
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GnomAD4 genome AF: 0.00000658 AC: 1AN: 152090Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74276
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
beta Thalassemia Pathogenic:2Other:1
Pathogenic, no assertion criteria provided | curation | The ITHANET community portal, The Cyprus Institute of Neurology and Genetics | Nov 25, 2019 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 14, 2022 | Disruption of this splice site has been observed in individuals with beta thalassemia (PMID: 2123063, 6583702). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 2 of the HBB gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. ClinVar contains an entry for this variant (Variation ID: 21190). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site is associated with altered splicing resulting in unknown protein product impact (PMID: 6583702). - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 08, 2021 | This variant (also known as IVS-II-849 (A>C)) is located in the canonical splice-acceptor site of intron 2 of the HBB gene, and disrupts normal splicing of the beta-globin mRNA. The variant is associated with beta(0)-thalassemia (PMID: 2424301 (1986)). It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. - |
Beta zero thalassemia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 1986 | - - |
Beta-thalassemia major Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 10, 2022 | Variant summary: HBB c.316-2A>C (also known as IVS II-849A>C in the literature) 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: Four predict the variant abolishes a canonical 3 prime acceptor site. However, these predictions have yet to be confirmed by functional studies. Blot hybridization analysis of RNA prepared from the erythoid cells of the patient who carried the variant and was diagnosed with HbS-beta0 thalassemia showed only RNA of normal size. The authors postulated that this may be attributed to the rapid degradation of the abnormal RNA or to the complete absence of an abnormally processed RNA (Padanilam et al, 1986). The variant was absent in 251048 control chromosomes (gnomAD). c.316-2A>C has been reported in the literature in at least an individual affected with Beta Thalassemia Major (Chouk_2004, Padanilam_1986). These data indicate that the variant is very likely to be associated with disease.Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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
GERP RS
Splicing
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Calibrated prediction
Score
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at