11-5227159-G-T
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4
The ENST00000647020.1(HBB):c.-138C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000905 in 552,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000090 ( 0 hom. )
Consequence
HBB
ENST00000647020.1 5_prime_UTR
ENST00000647020.1 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.75
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-5227159-G-T is Pathogenic according to our data. Variant chr11-5227159-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 393701.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Likely_pathogenic=1, Pathogenic=5, Uncertain_significance=1}. Variant chr11-5227159-G-T is described in Lovd as [Pathogenic].
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.42). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBB | ENST00000647020.1 | c.-138C>A | 5_prime_UTR_variant | 1/3 | P1 | ||||
HBB | ENST00000380315.2 | c.-18-120C>A | intron_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 0.00000905 AC: 5AN: 552662Hom.: 0 Cov.: 5 AF XY: 0.00000669 AC XY: 2AN XY: 298996
GnomAD4 exome
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5
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552662
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5
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2
AN XY:
298996
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:10Uncertain:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
beta Thalassemia Pathogenic:4Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Mar 27, 2018 | - - |
Pathogenic, no assertion criteria provided | curation | The ITHANET community portal, The Cyprus Institute of Neurology and Genetics | Nov 25, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 03, 2022 | The c.-138C>A variant in HBB (also known as -88C>A) has been reported in the homozygous and compound heterozygous state in numerous individuals with Beta Thalassemia (selected publications: Rund 1991 PMID: 1986379, Atroshi 2021 PMID: 34794358, Hassan 2014 PMID: 24880717, Turner 2016 PMID: 27756326, Ozkinay 2015 PMID: 26076395, El-Shanshory 2014 PMID: 25408857, Baysal 2011 PMID: 22074124, Sirdah 2013 PMID: 23321370, Vetter 1997 PMID: 9163586). It has been reported in ClinVar (Variation ID 393701) but was absent from large population databases. This variant lies in a known transcription binding site (CACCC box) where other clinically significant HBB variants (such as c.-140C>T, c.-138C>T, c.-137C>G and c.-137C>T) have been identified. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive beta thalassemia. ACMG/AMP Criteria applied: PM2_Supporting, PS4, PM1. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 07, 2021 | The HBB c.-138C>A variant (also known as -88C>A) not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant reduces the binding of transcription factors and causes decreased transcription of the beta-globin gene. In the published literature, the variant has been reported in individuals with beta(+)-thalassemia (PMIDs: 26948378 (2017), 26076395 (2015), 23321370 (2013), 20437613 (2010), 1986379 (1991)). - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 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 not present in population databases (gnomAD no frequency). This variant has been observed in individuals with β-thalassemia intermedia (PMID: 9163586, 21232998, 22180324, 25408857, 26076396). It has also been observed to segregate with disease in related individuals. This variant is also known as -88C>A in literature. ClinVar contains an entry for this variant (Variation ID: 393701). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 23, 2020 | - - |
Hemoglobinopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 01, 2018 | Variant summary: HBB c.-138C>A is located in the untranscribed region upstream of the HBB gene region. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant lies in a known transcription binding site (CACCC box) where other HBB variants (such as c.-140C>T, c.-138C>T, c.-137C>G and c.-137C>T) are known to be pathogenic for BTHAL ITMD. The variant was absent in 30972 control chromosomes (gnomAD). The variant, c.-138C>A, has been reported in the literature in multiple individuals affected with Beta Thalassemia (Rund_1991, El-Shanshory_2014, Baysal_2011, Sirdah_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
alpha Thalassemia;C0002895:Hb SS disease;C0005283:beta Thalassemia;C0700299:Heinz body anemia;C1840779:METHEMOGLOBINEMIA, BETA TYPE;C1841621:Fetal hemoglobin quantitative trait locus 1;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Beta-plus-thalassemia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1991 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Jan 18, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at