NM_000518.5:c.92+5G>C
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong
The NM_000518.5(HBB):c.92+5G>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 0.000292 in 1,612,226 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000518.5 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.000237 AC: 36AN: 152190Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000593 AC: 149AN: 251204Hom.: 0 AF XY: 0.000803 AC XY: 109AN XY: 135754
GnomAD4 exome AF: 0.000297 AC: 433AN: 1459918Hom.: 1 Cov.: 33 AF XY: 0.000439 AC XY: 319AN XY: 726420
GnomAD4 genome 0.000243 AC: 37AN: 152308Hom.: 1 Cov.: 32 AF XY: 0.000389 AC XY: 29AN XY: 74474
ClinVar
Submissions by phenotype
beta Thalassemia Pathogenic:10Other:1
Variant summary: The c.92+5G>C variant affects a non-conserved intronic nucleotide. Mutation taster predicts damaging outcome for this variant. 4/5 programs in Alamut predict a loss of canonical splicing donor site. ESE finder predicts that this variant may affect ESE site of SC35. This variant is found in 87/121280 control chromosomes at a frequency of 0.0007173, which does not exceed maximal expected frequency of a pathogenic allele (0.0111803). This variant has been reported in many affected individuals (both homozygotes and compound heterozygotes with another disease variant in trans) presented with phenotypes including BTHAL-MJR and BTHAL-ITM. Functional studies proved the aberrant RNA splicing products (Treisman_Nature_1983). In addition, multiple reputable databases classified this variant as pathogenic. Taken together, this variant was classified as a Pathogenic. -
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The c.92+5G>C variant in HBB has been reported, in the homozygous and compound heterozygous state, in numerous individuals with beta thalassemia major and beta thalassemia intermedia (selected references Kazazian 1984 PMID: 6714226, Muhammad 2017 PMID: 28635337, https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=824). It has been reported in ClinVar (Variation ID 15447) and has been identified in 35/4822 South Asian chromosomes by gnomAD (https://gnomad.broadinstitute.org). This variant is located in the 5' splice region. Computational tools predict a splicing impact and functional studies have shown it reduces or completelys deactivate the natural splice donor site in intron 1 and activates three cryptic splice donor sites (Treisman 1983 PMID: 6188062). Different splice variants at this residue (c.92+5G>A, c.92+5G>T) have been reported as pathogenic in ClinVar. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive beta thalassemia. ACMG/AMP Criteria applied: PM2_Supporting,PP3, PS3_Moderate, PM3_very strong. -
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The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.053%). Splice region variant. Functional studies provide moderate evidence that the variant has a damaging effect on the gene or gene product (PMID: 6188062). In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.82). The homozygous variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000015447). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
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NM_000518.4(HBB):c.92+5G>C(aka IVS-I-5) is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy and is associated with beta thalessemia. Sources cited for classification include the following: PMID: 6714226, 6188062, 19000664, 18294253, and 23348723. Classification of NM_000518.4(HBB):c.92+5G>C(aka IVS-I-5) 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. -
not provided Pathogenic:10
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Reported in association with beta thalassemia major and beta thalassemia intermedia when in the homozygous or compound heterozygous state, opposite of a second HBB variant (Kazazian et al., 1984; Baysal, et al., 2011; Al-Allawi et al., 2013; Chaudhary et al., 2016).; Non-canonical splice site variant demonstrated to reduce or completely deactivate the natural splice donor site in intron 1 and activate three cryptic splice donor sites (Treisman et al., 1983; Divoky et al., 1992); Different splice variants at this residue (c.92+5G>A; c.92+5G>T) have been reported as pathogenic in ClinVar and at GeneDx (ClinVar SCV# 15449; 15448; ClinVar); This variant is associated with the following publications: (PMID: 6188062, 23348723, 22975760, 6585831, 31714438, 25525159, 1463768, 6714226, 23826747, 20301599, 22074124, 27134826, 23234478, 27690257, 20132300, 19000664, 18294253, 27263053, 2004023, 16291734, 14576320, 28635337, 29651865, 31589614, 31890591, 9163586) -
The HBB c.92+5G>C variant (rs33915217, HbVar ID: 824), also known as IVS-I-5 (G->C), is reported in the literature in the homozygous and compound heterozygous state in multiple individuals affected with severe beta(+) thalassemia/ beta(0) thalassemia (Cheng 1984, Muhammad 2017, Panja 2016, Perea 2004, Yasmeen 2016, HbVar database and references therein). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 15447), and it is found in the South Asian population with an allele frequency of 0.47% (145/30,612 alleles) in the Genome Aggregation Database. Functional studies demonstrate that the variant causes aberrant splicing, leading to a significant reduction in full-length mRNA (Triesman 1983). Based on available information, the c.92+5G>C variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Cheng T et al. Beta-Thalassemia in Chinese: use of in vivo RNA analysis and oligonucleotide hybridization in systematic characterization of molecular defects. Proc Natl Acad Sci U S A. 1984 81(9):2821-5. PMID: 6585831 Muhammad R et al. Population-Based Genetic Study of beta-Thalassemia Mutations in Mardan Division, Khyber Pakhtunkhwa Province, Pakistan. Hemoglobin. 2017 Mar;41(2):104-109. PMID: 28635337 Panja A et al. Hb Midnapore [beta53(D4)Ala?Val; HBB: c.161C>T]: A Novel Hemoglobin Variant with a Structural Abnormality Associated with IVS-I-5 (G>C) (HBB: c.92+5G>C) Found in a Bengali Indian Family. Hemoglobin. 2016 Sep;40(5):300-303. PMID: 27690257 Perea FJ Molecular spectrum of beta-thalassemia in the Mexican population. Blood Cells Mol Dis. 2004 Sep-Oct;33(2):150-2. PMID: 15315794 Treisman R et al. Specific transcription and RNA splicing defects in five cloned beta-thalassaemia genes. Nature. 1983 302(5909):591-6. PMID: 6188062 Yasmeen H et al. The molecular characterization of Beta globin gene in thalassemia patients reveals rare and a novel mutations in Pakistani population. Eur J Med Genet. 2016 Aug;59(8):355-62. PMID: 27263053 -
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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. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs33915217, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individuals with beta thalassemia (PMID: 18294253, 19000664, 22392582, 23162295, 27263053). It is commonly reported in individuals of Pakistani and Indian ancestry (PMID: 18294253, 19000664, 22392582, 23162295, 27263053). This variant is also known as IVS-I-5, IVSI-5, and IVS1-5. ClinVar contains an entry for this variant (Variation ID: 15447). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 6188062). For these reasons, this variant has been classified as Pathogenic. -
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HBB: PM3:Very Strong, PM2:Supporting, PP3 -
Beta-thalassemia HBB/LCRB Pathogenic:6
The splice region c.92+5G>C variant in HBB gene has been reported previously in homozygous or compound heterozygous state in individual(s) affected with beta thalassemia (Yasmeen H et al., 2016). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (Treisman R et al., 1983). This variant is reported with the allele frequency of 0.05% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. This splice region variant in intron 1 affects the position five nucleotides downstream of exon 1. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant in HBB gene, the molecular diagnosis is not confirmed. -
The variant HBB:c.92+5G>C is beta zero type of mutation. When this variant present in homozygous or in compound heterozygous with other beta 0 / beta + mutation leads to severe anemia, The condition known as beta thalassemia. In homozygous condition the patient suffers with very low hemoglobin needing monthly transfusion, the patient often presented with hepatosplenomegaly, Iron overload. The frequency of the variant among thalassemia patient in Eastern India is 50.64 % 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] -
The splice region c.92+5G>C variant in HBB gene has been reported in homozygous or compound heterozygous state in individuals affected with beta thalassemia (Yasmeen et al. 2016). The c.92+5G>C variant is reported with the allele frequency of 0.06% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing, and studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (Treisman et al. 1983). For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant in the HBB gene, the molecular diagnosis is not confirmed. -
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 (OMIM). (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. This variant leads to the use of three cryptic splice sites, resulting in the formation of three abnormally spliced RNAs and a decreased amount of normally spliced RNA (PMID: 6188062). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v4: 466 heterozygotes, 2 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same non-canonical splice position have been observed in gnomAD (v4) (highest allele count: 2 heterozygotes, 0 homozygotes). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic by multiple clinical laboratories in ClinVar. This variant has also been observed in multiple unrelated homozygous and compound heterozygous individuals with beta-thalassemia, including at least four individuals who are compound heterozygous for this variant and p.(Ser10Valfs*14) (PMID: 27263053). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
A Homozygote Splice site region variant c.92+5G>C in Exon 1 of the HBB gene that results in the amino acid substitution was identified. The observed variant has a maximum allele frequency of 0.00059/0.00006% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (variant ID: 15447). This variant has previously been reported for beta-thalassemia by Treisman R, et, al., 1983. Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -
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Beta-plus-thalassemia Pathogenic:2
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Dominant beta-thalassemia Pathogenic:1
The observed splice region c.92+5G>C variant in HBB gene has been reported in homozygous and compound heterozygous states in multiple individuals affected with beta thalassemia Panja et al., 2016; Yasmeen et al., 2016; Muhammad et al., 2017. Experimental Studies demonstrate that the variant causes aberrant splicing, leading to a significant reduction in full-length mRNA Treisman et al., 1983. The c.92+5G>C variant is present with the allele frequency of 0.06% in the gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic multiple submissions. SpliceAI predicts a score of 0.82 for this variant. Loss of function variants in HBB gene have been previously reported to be disease causing Aldakeel et al., 2019. For these reasons, this variant has been classified as Pathogenic. -
Inborn genetic diseases Pathogenic:1
The c.92+5G>C intronic pathogenic mutation results from a G to C substitution 5 nucleotides after coding exon 1 in the HBB gene. This mutation has been detected in individuals with beta-thalassemia (Agarwal S et al. Int J Lab Hematol, 2010 Jun;32:369-72; Sivalingam M et al. Int J Lab Hematol, 2012 Aug;34:377-82; Sirdah MM et al. Blood Cells Mol. Dis., 2013 Apr;50:247-51). In addition, this mutation showed reduced splicing efficiency with approximately half of the amount of RNA compared to wild type (Treisman R et al. Nature, 1983 Apr;302:591-6). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
HBB-related disorder Pathogenic:1
The HBB c.92+5G>C variant is predicted to interfere with splicing. This variant is predicted to alter splicing based on available splicing prediction programs (Alamut Visual Pus v.1.6.1) and functional studies have shown aberrant splicing (Treisman et al. 1983. PubMed ID: 6188062). This variant has been reported in many affected individuals with Beta thalassemia (Treisman et al. 1983. PubMed ID: 6188062; Kazazian et al. 1984. PubMed ID: 6714226; Muhammad et al 2017. PubMed ID: 28635337; Susanto et al. 2019. PubMed ID: 31890591). This variant is reported in 0.47% of alleles in individuals of South Asian descent in gnomAD and is reported to be pathogenic by several other labs (https://www.ncbi.nlm.nih.gov/clinvar/variation/15447/). 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
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Malaria, susceptibility to Pathogenic:1
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Beta-thalassemia major Pathogenic:1
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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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Hereditary persistence of fetal hemoglobin Pathogenic:1
The missense c.92+5G>C variant in HBB gene has been reported in heterozygous state in multiple individuals affected with Beta thalassemia (Hidayati NI, et. al., 2020; Yasmeen H,et. al., 2016). Functional studies demonstrate that the variant has a damaging effect on the gene or gene product (Treisman R, et. al.,1983). The c.92+5G>C variant is reported with an allele frequency of 0.05% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at