rs33941377
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The ENST00000647020.1(HBB):c.-137C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 706,420 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 Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., 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: 3.42
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 11-5227158-G-A is Pathogenic according to our data. Variant chr11-5227158-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 36287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5227158-G-A is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.43). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
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Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HBB | ENST00000647020.1 | c.-137C>T | 5_prime_UTR_variant | 1/3 | ENSP00000494175 | P1 | ||||
HBB | ENST00000380315.2 | c.-18-119C>T | intron_variant | 5 | ENSP00000369671 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000902 AC: 5AN: 554166Hom.: 0 Cov.: 5 AF XY: 0.0000100 AC XY: 3AN XY: 299838
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152254Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74452
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5Other: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 | May 08, 2023 | The HBB c.-137C>T variant (rs33941377, HbVarID: 759), also known as -87C>T, is reported in the literature in several individuals with beta thalassemia intermedia, both of whom carried an additional pathogenic variant (Kulozik 1991, Gallagher 2016, HbVar database). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant is located in HBB promoter in the CACCC box that promotes gene transcription, and functional assays indicate that this variant results in reduced transcriptional activity (Kulozik 1991). Based on available information, this variant is considered pathogenic. References: Link to HbVar: https://globin.bx.psu.edu/hbvar/menu.html Gallagher PG et al. Mutation in a Highly Conserved COOH-Terminal Residue of Kruppel-Like Factor 1 Associated with Elevated Hb F in a Compound Heterozygous beta-Thalassemia Patient with a Nontransfusion-Dependent Thalassemia Phenotype. Hemoglobin. 2016 Sep;40(5):361-364. PMID: 27821015. Kulozik AE et al. Thalassemia intermedia: moderate reduction of beta globin gene transcriptional activity by a novel mutation of the proximal CACCC promoter element. Blood. 1991 May 1;77(9):2054-8. PMID: 2018842. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 22, 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 individual(s) with autosomal recessive beta-thalassemia (PMID: 2018842, 20524821, 27821015). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as -87C>T. ClinVar contains an entry for this variant (Variation ID: 36287). Studies have shown that this variant alters HBB gene expression (PMID: 2018842). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 14, 2023 | Published functional studies demonstrate a damaging effect, as transfection of the gene with c.-137C>T in HeLa cells showed a reduction of beta globin gene transcriptional activity (Kulozik et al., 1991; Kircher et al., 2019); Also known as -87C>T; No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 11857746, 2018842, 20524821, 31395865, 27821015, 9163586, 21119755, 21423179, 1550780) - |
Beta thalassemia intermedia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 30, 2023 | Variant summary: HBB c.-137C>T is located in the untranscribed region upstream of the HBB gene region. The variant was absent in 31398 control chromosomes. Ithanet lists this variant in association with + phenotype with relative carrier frequencies as follow: Czech Republic 2%, Slovakia 2%, Germany 1%, United Kingdom 0.2%, Italy 0.1%, and India 0.04%. The variant was found in multiple patients with symptoms ranging from beta-thalassemia major to beta-thalassemia intermedia depending on the second variant in trans and/or presence of alteration in genes encoding a-chain. Functional studies have shown that this variant leads to reduced transcription rate and synthesis of HBB (Kulozik_1991). The following publications have been ascertained in the context of this evaluation (PMID: 2018842, 11857746, 21119755, 21423179, 20524821, 27821015, 1550780). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Hb SS disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
beta Thalassemia Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
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Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at