rs33952266
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000518.5(HBB):c.316-1G>T variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00000137 in 1,461,790 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 Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
HBB
NM_000518.5 splice_acceptor
NM_000518.5 splice_acceptor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 7.10
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 22 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease,
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 11-5225727-C-A is Pathogenic according to our data. Variant chr11-5225727-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5225727-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBB | NM_000518.5 | c.316-1G>T | splice_acceptor_variant | ENST00000335295.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBB | ENST00000335295.4 | c.316-1G>T | splice_acceptor_variant | 1 | NM_000518.5 | P1 | |||
HBB | ENST00000647020.1 | c.316-1G>T | splice_acceptor_variant | P1 | |||||
HBB | ENST00000633227.1 | c.*132-1G>T | splice_acceptor_variant, NMD_transcript_variant | 3 | |||||
HBB | ENST00000475226.1 | n.248-1G>T | splice_acceptor_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461790Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727214
GnomAD4 exome
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2
AN:
1461790
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31
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0
AN XY:
727214
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
Bravo
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
beta Thalassemia Pathogenic:2
Pathogenic, no assertion criteria provided | curation | The ITHANET community portal, The Cyprus Institute of Neurology and Genetics | Nov 25, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 07, 2019 | Variant summary: HBB c.316-1G>T 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. 5/5 computational tools predict that the variant significantly impacts normal splicing by abolishing a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251150 control chromosomes (gnomAD). c.316-1G>T has been reported in the literature in individuals affected with Beta Thalassemia (Najmabadi_2002). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar (after 2014) and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 23, 2016 | - - |
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
MutationTaster
Benign
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at