rs35724775
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000518.5(HBB):c.92+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000738 in 1,612,160 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 Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000072 ( 1 hom. )
Consequence
HBB
NM_000518.5 splice_region, intron
NM_000518.5 splice_region, intron
Scores
2
Splicing: ADA: 0.9397
1
1
Clinical Significance
Conservation
PhyloP100: 1.09
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 11-5226924-A-G is Pathogenic according to our data. Variant chr11-5226924-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5226924-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000920 AC: 14AN: 152138Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000119 AC: 30AN: 251332Hom.: 0 AF XY: 0.000184 AC XY: 25AN XY: 135830
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GnomAD4 exome AF: 0.0000719 AC: 105AN: 1459904Hom.: 1 Cov.: 33 AF XY: 0.0000854 AC XY: 62AN XY: 726418
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GnomAD4 genome 0.0000920 AC: 14AN: 152256Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74450
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:26Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
beta Thalassemia Pathogenic:8Other:1
| Pathogenic, no assertion criteria provided | clinical testing | Baylor Genetics | Jul 01, 2015 | Our laboratory reported dual molecular diagnoses in HBB (NM_000518.4, c.92+6T>C) and TJP2 (NM_004817.3, c.1243delT homozygous) in one individual with reported features that include prematurity, cholestasis of the liver, mild pulmonic stenosis, chronic anemia of thalassemia, and obstructive sleep apnea. The HBB variant has been previously reported as disease-causing (PMID 20395516, 21797703, 21228398). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Feb 21, 2020 | PS3, PS4, PM3, PP3, PP4, PP5 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 02, 2023 | The c.92+6T>C variant (formerly known as IVS-I-6) in HBB has been reported in the homozygous state in at least 38 individuals with beta thalassemia and in the compound heterozygous state with another pathogenic HBB variant in at least 36 individuals with beta thalassemia (Jalilian 2017 PMID: 28391758, Fernandes 2011 PMID: 21797703, El-Latif 2002 PMID: 11939510, Danjou 2015 PMID: 25480500, Chen 2015 PMID: 25856402, Carrocini 2017 PMID: 28366028). It has also been identified in 0.95% (3/316) of Middle Eastern chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is still compatible with a recessive allele frequency for a common condition. This variant has also been reported in ClinVar (Variation ID 15450). This variant disrupts the canonical splice donor site of intron 1. Functional assays show that this variant results in aberrant splicing of the first and second exons of HBB, leading to production of non-functional mRNA and reduction of wildtype transcripts (Breveglieri 2015 PMID: 26097845). Loss of function of the HBB gene is an established disease mechanism in autosomal recessive beta thalassemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive beta thalassemia. ACMG/AMP Criteria applied: PVS1_Strong, PS3, PM3_VeryStrong. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion, Medical Genetics | May 22, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.011%). Splice region variant predicted to alter splicing. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000015450). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| 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 | Myriad Genetics, Inc. | Dec 09, 2019 | NM_000518.4(HBB):c.92+6T>C(aka IVS-I-6T>C) is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy; it is associated with beta thalassemia and is classified as a beta-plus variant. Sources cited for classification include the following: PMID 7522523, 2200760, and 23321370. Classification of NM_000518.4(HBB):c.92+6T>C(aka IVS-I-6T>C) 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, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 14, 2018 | The HBB c.92+6T>C variant, widely known as IVS-I-6, is a well-described and common cause of beta thalassemia, with the greatest frequency among Mediterranean and Middle-Eastern populations, accounting for up to 48.5 percent of disease alleles in some populations (El-Latif et al. 2002; Origa et al. 2015). Individuals who are homozygous or compound heterozygous for the c.92+6T>C variant display a range of disease phenotypes from beta thalassemia intermedia to beta thalassemia major (El-Latif et al. 2002; Origa et al. 2015). Across a selection of available literature, the c.92+6T>C variant has been identified in a homozygous state in at least 42 patients and in a compound heterozygous state with a second pathogenic variant in at least 21 individuals, with symptoms ranging from non-transfusion dependent beta thalassemia to transfusion dependent beta thalassemia major (El-Latif et al. 2002; Kakavas et al. 2006; El-Gawhary et al. 2007; Bell et al. 2011). Control data are unavailable for the c.92+6T>C variant, which is reported at a frequency of 0.00046 in the Other population of the Genome Aggregation Database. RT-PCR experiments demonstrated that the c.92+6T>C variant produces aberrantly spliced mRNA transcripts in samples derived from homozygous patients or a transgenic mouse line (TG-β-IVSI-6) (Breveglieri et al. 2015). Haplotype analysis has also shown the c.92+6T>C variant is linked to two beta-globin cluster haplotypes, Mediterranean VI and VII (El-Latif et al. 2002; Chen et al. 2015). Based on the collective evidence, the c.92+6T>C variant is classified as pathogenic for beta thalassemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
not provided Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 19, 2024 | The HBB c.92+6T>C variant (rs35724775, ClinVar ID: 15450, HbVar ID: 826), also known as IVS-I-6 T>C, 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 (El-Latif 2002, HbVar database and references therein). This variant disrupts the canonical splice donor site of intron 1, and functional assays show aberrant splicing of the first and second exons of HBB, leading to production of non-functional beta globin mRNA and reduction of wildtype transcripts (Breveglieri 2015). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Breveglieri G et al. Generation and Characterization of a Transgenic Mouse Carrying a Functional Human beta-Globin Gene with the IVSI-6 Thalassemia Mutation. Biomed Res Int. 2015:687635. PMID: 26097845. Carrocini GCS et al. Mutational Profile of Homozygous beta-Thalassemia in Rio de Janeiro, Brazil. Hemoglobin. 2017 Jan;41(1):12-15. PMID: 28366028. El-Latif MA et al. The beta+-IVS-I-6 (T-->C) mutation accounts for half of the thalassemia chromosomes in the Palestinian populations of the mountain regions. Hemoglobin. 2002 Feb;26(1):33-40. PMID: 11939510. 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 17, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Mar 04, 2025 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 09, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 23, 2024 | Published functional studies demonstrate that this variant results in aberrantly spliced mRNAs (PMID: 26097845); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 21228398, 23348723, 25525159, 22975760, 6280057, 25856402, 27959697, 25825561, 26372288, 28391758, 28670940, 28366028, 34426522, 31589614, 9163586, 31286593, 2577233, 28060121, 28399358, 33947296, 34794358, 9629495, 34272389, 20301599, 38468841, 39062234, 38112059, 38397898, Kacmaz2024, 26097845) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 25, 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. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs35724775, gnomAD 0.02%). This variant has been observed in individuals with beta thalassemia (PMID: 2200760, 7668219, 21797703, 25856402, 28366028, 28391758, 28670940). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS-1-VI and IVS-I-6 T>C. ClinVar contains an entry for this variant (Variation ID: 15450). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in alternative splicing and introduces a premature termination codon (PMID: 26097845). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2018 | - - |
Beta-thalassemia HBB/LCRB Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 11, 2024 | Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with HBB-related hemoglobinopathies, including beta thalassemia (OMIM). Dominant negative is also a suggested mechanism (PMID: 29700171). (I) 0108 - This gene is associated with both recessive and dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Variable severity has been reported in sickle cell patients carrying the same variants (PMID: 31788855). In addition, clinical severity of beta-thalassemia patients is also dependent on whether variants in HBB are heterozygous, homozygous or compound heterozygous, and the amount of residual protein that is expressed (PMID: 20301599). (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. Mouse study showed that the splice variant created 3 different possible cryptic GT splicing sites, two of which are NMD predicted (PMID: 26097845). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v4; 117 heterozygotes, 1 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4; 1 heterozygote, 0 homozygotes). (I) 0508 - In silico predictions for abnormal splicing are conflicting. (I) 0710 - Another non-canonical splice variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. c.92+6T>A has been classified as a variant of uncertain significance by one clinical laboratory (ClinVar). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been classified as pathogenic and likely pathogenic by many clinical laboratories (ClinVar) and has been reported in individuals with beta thalassemia (PMID: 32420772). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Jun 22, 2023 | The splice region c.92+6T>C variant in HBB gene has been observed in multiple individuals with beta thalassemia Hussain et. al., 2017; Jalilian et. al., 2017. It has also been observed to segregate with disease in related individuals. This variant is also known as IVS-1-VI and IVS-I-6 T>C. Studies have shown that this variant results in alternative splicing and introduces a premature termination codon Breveglieri et. al., 2015. The resulting mRNA is expected to undergo nonsense-mediated decay. The observed variant has allele frequency of 0.01% in gnomAD exomes database. This variant has been submitted to the ClinVar database as Uncertain Significance / Likely Pathogenic / Pathogenic multiple submissions. SpliceAI predicts 0.4300 score for this variant. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing Buratti et. al., 2007. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 22, 2015 | The c.92+6T>C (also known as IVS1-6T>C in the literature) intronic pathogenic mutation results from a T to C substitution 6 nucleotides after coding exon 1 in the HBB gene. This mutation is a prevalent pathogenic mutation in the Mediterranean population (Origa R. Beta-Thalassemia. 2000 Sep 28 [Updated 2015 May 14]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1426/). In one study of patients from three countries of the Mediterranean basin (Italy, France, Malta), this mutation was reportedly detected in conjunction with the p.Q40* (c.118C>T) pathogenic mutation in HBB in 4.1% of 890 beta-thalassemia patients (Danjou F, Haematologica 2015 Apr; 100(4):452-7). This mutation accounted for 31% of alleles in a small Brazilian beta-thalassemia population (Fernandes AC, Hemoglobin 2011 ; 35(4):358-66). Based on the supporting evidence, c.92+6T>C is interpreted as a disease-causing mutation. - |
Heinz body anemia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
HBB-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 12, 2023 | The HBB c.92+6T>C variant is predicted to interfere with splicing. This variant has previously been reported to be causative for autosomal recessive beta-thalassemia (see for example Orkin et al. 1982. PubMed ID: 6280057; Makhoul et al. 2005. PubMed ID: 15638828). This variant is reported in 0.021% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-5248154-A-G). This variant is interpreted 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
| 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 | research | Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Mar 25, 2024 | - - |
Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:METHEMOGLOBINEMIA, BETA TYPE;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6;CN322236:Beta-thalassemia HBB/LCRB Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 27, 2024 | - - |
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 | Apr 15, 1982 | - - |
Computational scores
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BayesDel_noAF
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dbscSNV1_ADA
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dbscSNV1_RF
Pathogenic
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Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 22
DS_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at