rs35004220
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000518.5(HBB):c.93-21G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,608,186 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 Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 0 hom. )
Consequence
HBB
NM_000518.5 intron
NM_000518.5 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.0740
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 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-5226820-C-T is Pathogenic according to our data. Variant chr11-5226820-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5226820-C-T is described in Lovd as [Pathogenic]. Variant chr11-5226820-C-T is described in Lovd as [Pathogenic]. Variant chr11-5226820-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| HBB | NM_000518.5 | c.93-21G>A | intron_variant | ENST00000335295.4 | NP_000509.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| HBB | ENST00000335295.4 | c.93-21G>A | intron_variant | 1 | NM_000518.5 | ENSP00000333994 | P1 |
Frequencies
GnomAD3 genomes 0.0000986 AC: 15AN: 152100Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000155 AC: 39AN: 250944Hom.: 0 AF XY: 0.000184 AC XY: 25AN XY: 135630
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GnomAD4 exome AF: 0.000125 AC: 182AN: 1456086Hom.: 0 Cov.: 34 AF XY: 0.000134 AC XY: 97AN XY: 724710
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GnomAD4 genome 0.0000986 AC: 15AN: 152100Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74300
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:30Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:10
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 10, 2021 | In vitro RNA and functional studies demonstrate a damaging effect with the creation of an alternative splice site causing abnormal gene splicing (Busslinger et al., 1981).; Also known as IVS-I-110G>A; This variant is associated with the following publications: (PMID: 6264391, 21797703, 25087612, 22975760, 28670940, 27979672, 31456457, 31130284, 21228398, 26372288, 1967205, 26016902, 1390250, 6895866, 6264477, 28391758, 28366028, 28667000, 14555304, 9163586, 31589614, 15609277, 9629495, 12702481, 2577233) - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 24, 2023 | The HBB c.93-21G>A variant (rs35004220, ClinVar ID: 15454, HbVar ID: 827), also known as IVS-I-110 G>A, is reported in the literature in multiple individuals affected with beta+ thalassemia (Carrocini 2017, Hussain 2017, Jalilian 2017). This variant is one of the most common beta-thalassemia alleles in Mediterranean and Middle-Eastern countries (Kaplan 1990, HbVar database and references therein). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Carrocini GCS et al. Mutational Profile of Homozygous beta-Thalassemia in Rio de Janeiro, Brazil. Hemoglobin. 2017 Jan;41(1):12-15. PMID: 28366028. Hussain A et al. Rare beta-Globin Gene Mutations in Pakistan. Hemoglobin. 2017 Mar;41(2):100-103. PMID: 28670940. Jalilian M et al. The Frequency of HBB Mutations Among beta-Thalassemia Patients in Hamadan Province, Iran. Hemoglobin. 2017 Jan;41(1):61-64. PMID: 28391758. Kaplan F et al. Beta-thalassemia genes in French-Canadians: haplotype and mutation analysis of Portneuf chromosomes. Am J Hum Genet. 1990 46(1):126-32. PMID: 1967205. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 22, 2024 | This sequence change falls in intron 1 of the HBB gene. It does not directly change the encoded amino acid sequence of the HBB protein. This variant is present in population databases (rs35004220, gnomAD 0.03%). This variant has been observed in individual(s) with HBB-related conditions (PMID: 1967205, 2200760, 28366028, 28391758). 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 IVS-I-110G>A. ClinVar contains an entry for this variant (Variation ID: 15454). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 27, 2021 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Jun 24, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | HBB: PM3:Very Strong, PM2, PP4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Jul 23, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 21, 2022 | - - |
beta Thalassemia Pathogenic:9Other:1
| Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 02, 2023 | The heterozygous c.93-21G>A variant in HBB was identified by our study in four affected members of one family with beta thalassemia. The c.93-21G>A variant in HBB has been identified in over 160 individuals with beta thalassemia (‚Äã‚ÄãPMID: 6264477, PMID: 6264391, PMID: 24106605, PMID: 28391758, PMID: 1390250, PMID: 2200760), but has been identified in 0.03% (37/128830) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs35004220). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 15454) and has been interpreted as pathogenic by multiple submitters. Of these 160 individuals, 138 were homozygotes (PMID: 1390250, PMID: 28391758, PMID: 24106605, PMID: 2200760), and 11 were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 2200760, ClinVar Variation ID: 15436, ClinVar Variation ID: 15402, ClinVar Variation ID: 15457, ClinVar Variation ID: 15239; PMID: 6264391, ClinVar Variation ID: 15060; PMID: 24106605, ClinVar Variation ID: 15402, ClinVar Variation ID: 15415), which increases the likelihood that the c.93-21G>A variant is pathogenic. RT-PCR analysis of RNA from affected tissue shows evidence of altered splicing of exon 2, resulting in 19bp insertion, frameshift, and premature truncation (PMID: 16421096); altered splicing was also seen in HeLa cells (PMID: 6895866) and in a humanized mouse model (PMID: 16421096). This variant is located in the 3' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive beta thalassemia. ACMG/AMP Criteria applied: PS3, PM2_Supporting, PM3_VeryStrong (Richards 2015). - |
| 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 | Genome-Nilou Lab | May 12, 2021 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Mar 22, 2022 | The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 28391758, 28366028, 2200760). It was observed to be in trans with the other variant (3billion dataset). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000015454). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0001668). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Apr 06, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 03, 2022 | The c.93-21G>A variant in HBB, also known as IVS-I-110 G>A, has been reported in numerous individuals with beta-thalassemia and is one of the most common beta-thalassemia alleles in Mediterranean and Middle-Eastern countries (Kaplan 1990 PMID: 1967205, (Carrocini 2017 PMID: 28366028, Hussain 2017 PMID: 28670940, Jalilian 2017 PMID: 28391758, Baysal 1992 PMID: 1390250) https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=827). It has also been reported in ClinVar (Variation ID 15454) and has been identified in 14/68028 European chromosomes by gnomAD (https://gnomad.broadinstitute.org). In vitro functional studies support an impact on splicing (Busslinger 1981 PMID: 6895866). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive beta thalassemia. ACMG/AMP Criteria applied: PM2_Supporting, PS3_Moderate, PM3_very strong. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Oct 18, 2019 | NM_000518.4(HBB):c.93-21G>A is classified as pathogenic and is associated with beta thalassemia. Sources cited for classification include the following: PMID 2200760, 1390250, 8330981, 1967205, 1390250, 2200760, 6264477, 6264391. Classification of NM_000518.4(HBB):c.93-21G>A is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
| Pathogenic, no assertion criteria provided | clinical testing | Pediatric Molecular Hematology, Schneider Children's Medical Center of Israel | - | - - |
Beta-thalassemia HBB/LCRB Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jan 17, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Intergen, Intergen Genetics and Rare Diseases Diagnosis Center | - | - - |
| Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Aug 29, 2022 | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 31, 2015 | The c.93-21G>A pathogenic mutation (also known as IVS1-110G>A), located in coding intron 1 of the HBB gene, results from a G>A substitution 21 nucleotides before coding exon 2. This mutation was first described in an individual of Turkish Cypriot origin with severe thalassemia intermedia who was compound heterozygous for another pathogenic HBB mutation (Westaway D, Williamson R. Nucleic Acids Res. 1981;9:1777-1788). In a population of Turkish patients affected with beta thalassemia major, 33 individuals were homozygous for this pathogenic mutation and the allele frequency in some Turkish subpopulations is as high as 75% of disease alleles (Fettah A et al. Mediterr J Hematol Infect Dis. 2013;5(1):e2013055 and Baysal et al. Br J Haematol. 1992;81(4):607-9. ). RT-PCR studies from mRNA in both human samples and mouse models demonstrated the presence of aberrant splicing, with 90% of transcripts with abnormal splicing in homozygous mice (Vadolas J. J Biol Chem. 2006 Mar 17;281(11):7399-405). Based on the supporting evidence, c.93-21G>A is interpreted as a disease-causing mutation. - |
Fetal hemoglobin quantitative trait locus 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | This variant was identified as compound heterozygous. - |
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
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Malaria, susceptibility to Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
Beta-thalassemia major Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing;curation | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2011 | - - |
Hb SS disease Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Beta-plus-thalassemia Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1990 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at