chr11-5226929-C-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000518.5(HBB):c.92+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000279 in 1,612,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000518.5 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152224Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000716 AC: 18AN: 251366Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135846
GnomAD4 exome AF: 0.0000294 AC: 43AN: 1460538Hom.: 0 Cov.: 33 AF XY: 0.0000427 AC XY: 31AN XY: 726710
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152224Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74360
ClinVar
Submissions by phenotype
not provided Pathogenic:6
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Reported previously in association with beta-thalassemia (Kazazian et al., 1984; Varawalla et al., 1991; Yasmeen et al., 2016); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 8199027, 16044458, 10975438, 2064964, 26865073, 26715484, 26554253, 22975760, 25525159, 10870879, 9225979, 18294253, 26291967, 12885342, 19090545, 18759082, 19000664, 19843386, 19254853, 28635337, 6714226, 27263053, 30275481, 9629495, 31890591, 9163586, 8012089) -
The HBB c.92+1G>T variant (rs33971440, HbVar ID: 818) is predicted to cause a loss of the canonical donor splice site and has been associated with beta(0) thalassemia (see HbVar link, Kazazian 1984); therefore this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Kazazian HH Jr et al. (1984) Molecular characterization of seven beta-thalassemia mutations in Asian Indians. EMBO J. 3(3):593-6. PMID: 6714226 -
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This sequence change affects a donor splice site in intron 1 of the HBB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309). This variant is present in population databases (rs33971440, gnomAD 0.06%). Disruption of this splice site has been observed in individuals with autosomal recessive beta thalassemia (PMID: 9450794, 22335963, 25849334, 27263053, 29695942). It is commonly reported in individuals of South Asian ancestry (PMID: 9450794, 22335963, 27263053). This variant is also known as "IVS1-1 G-T". ClinVar contains an entry for this variant (Variation ID: 15437). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
beta Thalassemia Pathogenic:4
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Variant summary: HBB c.92+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. The variant allele was found at a frequency of 7.2e-05 in 251366 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in HBB causing Beta Thalassemia (7.2e-05 vs 0.011), allowing no conclusion about variant significance. c.92+1G>T has been reported in the literature in numerous individuals affected with Beta Thalassemia. These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Beta zero thalassemia Pathogenic:1
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Inborn genetic diseases Pathogenic:1
The c.92+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 1 of the HBB gene. This mutation was reported in an infant with beta thalassemia major in conjunction with a second HBB alteration (Garewal G et al. Am. J. Hematol., 2005 Aug;79:252-6). This mutation is a common cause of beta thalassenia and results in beta-zero thalassemia (Chan OT et al. Am. J. Clin. Pathol., 2010 May;133:700-7; Sivalingam M et al. Int J Lab Hematol, 2012 Aug;34:377-82). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -
HBB-related disorder Pathogenic:1
The HBB c.92+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant, previously described as IVS I -1G>T, has been reported to be causative for beta-thalassemia with highest frequencies for the variant being found in Indian and Thai populations (Edison et al. 2008. PubMed ID: 18294253; Muhammad et al. 2017. PubMed ID: 28635337; Kazazian et al 1984. PubMed ID: 6714226; http://ccg.murdoch.edu.au/thalind/variants.php). Another substitution at the same position, c.92+1G>A, has also been found in individuals with beta-thalassemia (Faustino et al. 1992. PubMed ID: 1634236; Waye et al. 2002. PubMed ID: 11939519). This variant is reported in 0.059% of alleles in individuals of South Asian descent in gnomAD. Variants that disrupt the consensus splice donor site in HBB are expected to be pathogenic. The c.92G>T variant is interpreted as pathogenic. -
Beta-thalassemia HBB/LCRB Pathogenic:1
The variant HBB:c.92+1G>Tis beta0 type of mutation.The variant introduce a premature termination codon. When this variant present with other pathogenic HBB mutation leads to severe type of thalassemia. Patients needing blood transfusion, often presented with hepatosplenomegaly, Iron overload. The frequency of the variant among thalassemia patient in Eastern India is 0.09 % as per our multicentric project - A Genetic Diagnostic Algorithm Based Study for Thalassemia in Northern and Eastern Indian Populations, Funded by Dept. of Biotechnology , Govt of India [Project No. BT/PR26461/MED/12/821/2018] -
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
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Hb SS disease Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at