rs34305195
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_000518.5(HBB):βc.-50A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 1,232,076 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (β β ).
Frequency
Genomes: π 0.000013 ( 0 hom., cov: 33)
Exomes π: 0.000073 ( 1 hom. )
Consequence
HBB
NM_000518.5 5_prime_UTR
NM_000518.5 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.523
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 Likely_pathogenic. Variant got 9 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-5227071-T-G is Pathogenic according to our data. Variant chr11-5227071-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 36292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5227071-T-G is described in Lovd as [Pathogenic]. Variant chr11-5227071-T-G is described in Lovd as [Likely_pathogenic].
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.46). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBB | NM_000518.5 | c.-50A>C | 5_prime_UTR_variant | 1/3 | ENST00000335295.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBB | ENST00000335295.4 | c.-50A>C | 5_prime_UTR_variant | 1/3 | 1 | NM_000518.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152210Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000104 AC: 26AN: 249250Hom.: 0 AF XY: 0.000148 AC XY: 20AN XY: 134686
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GnomAD4 exome AF: 0.0000732 AC: 79AN: 1079866Hom.: 1 Cov.: 15 AF XY: 0.000114 AC XY: 63AN XY: 555048
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 14, 2023 | The HBB c.-50A>C variant (rs33915217, HbVarID: 770), also known as CAP +1 (A>C), is reported in the literature in individuals affected with beta thalassemia either in the homozygous state or in trans to another pathogenic HBB variant (Garewal 2007, Wong 1987, HbVar database). In the heterozygous state, the c.-50A>C variant is considered βsilentβ and is associated with only minor hematological abnormalities, if any (Khattak 2012). This variant is reported as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variation ID: 36292), and is found in the South Asian population with an allele frequency of 0.085% (26/30,504 alleles) in the Genome Aggregation Database. This variant occurs in the 5' untranslated region at a nucleotide that is moderately conserved. Based on available information, the c.-50A>C variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Garewal G et al. The clinical significance of the spectrum of interactions of CAP+1 (A-->C), a silent beta-globin gene mutation, with other beta-thalassemia mutations and globin gene modifiers in north Indians. Eur J Haematol. 2007 Nov;79(5):417-21. PMID: 17900295. Khattak SA et al. Prevalence of various mutations in beta thalassaemia and its association with haematological parameters. J Pak Med Assoc. 2012 Jan;62(1):40-3. PMID: 22352100. Wong C et al. Characterization of beta-thalassaemia mutations using direct genomic sequencing of amplified single copy DNA. Nature. 1987 Nov 26-Dec 2;330(6146):384-6. PMID: 3683554. - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 30, 2021 | The frequency of this variant in the general population, 0.00085 (26/30504 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant is associated with mild beta (+)-thalassemia (PMID: 3683554 (1987), 22335963 (2012), 27263053 (2016), 32722952 (2020), 33491330 (2021)). Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 28, 2023 | This variant occurs in a non-coding region of the HBB gene. It does not change the encoded amino acid sequence of the HBB protein. This variant is present in population databases (rs34305195, gnomAD 0.08%). This variant has been observed in individuals with beta thalassemia (PMID: 19254853, 22335963, 27263053). This variant is also known as the "Cap+1" or "Cap site+1" variant. ClinVar contains an entry for this variant (Variation ID: 36292). Studies have shown that this variant alters HBB gene expression (PMID: 3683554). For these reasons, this variant has been classified as Pathogenic. - |
beta Thalassemia Pathogenic:2Other:1
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Feb 10, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 08, 2017 | Variant summary: The HBB c.-50A>C (also known as CAP +1 A>C) variant involves the alteration of a non-conserved nucleotide, which lies in the CAP-site from where transcription starts. One in silico tool predicts a damaging outcome for this variant. This variant was found in 12/119792 control chromosomes at a frequency of 0.0001002, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). The variant was reported in numerous Beta Thalassemia patients individuals in the literature. Taken together, this variant is classified as pathogenic. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Beta-plus-thalassemia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 26, 1987 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
La Branchor
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BranchPoint Hunter
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at