Variant summary: HBB c.93-3T>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 5' splicing donor site. Three predict the variant weakens the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 252420 control chromosomes. c.93-3T>G has been reported in the literature in multiple individuals affected with Beta Thalassemia Intermedia (example, Wong_1989, Chiou_1993, Ho_1998, Sinha_2009, Al-Allawi_2014, Hassan_2015, Hussain_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The The ITHANET community portal has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000518.5(HBB):c.93-3T>G
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(7)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000518.5(HBB):c.93-3T>G
Variation ID: 36341 Accession: VCV000036341.17
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11p15.4 11: 5226802 (GRCh38) [ NCBI UCSC ] 11: 5248032 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Feb 20, 2024 Jan 24, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000518.5:c.93-3T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000011.10:g.5226802A>C NC_000011.9:g.5248032A>C NG_000007.3:g.70814T>G NG_042296.1:g.333A>C NG_046672.1:g.4737A>C NG_059281.1:c.93-3T>G NG_059281.1:g.5270T>G LRG_1232:g.5270T>G LRG_1232t1:c.93-3T>G - Protein change
- -
- Other names
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IVS I-128 (T>G)
IVS1-128T>G
IVS1, T-G, -3
- Canonical SPDI
- NC_000011.10:5226801:A:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00001
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| HBB | - | - |
GRCh38 GRCh37 |
22 | 1835 | |
| LOC106099062 | - | - | - | GRCh38 | - | 863 |
| LOC107133510 | - | - | - | GRCh38 | - | 1785 |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (1) |
no assertion criteria provided
|
Mar 1, 1989 | RCV000016710.36 | |
| Pathogenic (3) |
no assertion criteria provided
|
Mar 25, 2021 | RCV000030011.13 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 2, 2022 | RCV002222330.9 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 24, 2023 | RCV002477023.9 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Mar 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Beta thalassemia intermedia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052666.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 23, 2022 |
Comment:
Variant summary: HBB c.93-3T>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: HBB c.93-3T>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 5' splicing donor site. Three predict the variant weakens the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 252420 control chromosomes. c.93-3T>G has been reported in the literature in multiple individuals affected with Beta Thalassemia Intermedia (example, Wong_1989, Chiou_1993, Ho_1998, Sinha_2009, Al-Allawi_2014, Hassan_2015, Hussain_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The The ITHANET community portal has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Aug 20, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002774341.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
The variant found in at least one symptomatic individual. The variant is predicted to negatively affect a known splice site. The variant occurs in multiple … (more)
The variant found in at least one symptomatic individual. The variant is predicted to negatively affect a known splice site. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and several have a phenotype known to be consistent with disease. (less)
|
|
|
Likely pathogenic
(Jan 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004563859.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The HBB: c.93-3T>G variant (also known as IVS-I-128 (T->G), rs34527846, HbVar ID: 829) is reported in the compound heterozygous state in individuals with beta (+) … (more)
The HBB: c.93-3T>G variant (also known as IVS-I-128 (T->G), rs34527846, HbVar ID: 829) is reported in the compound heterozygous state in individuals with beta (+) thalassemia (Chiou 1993, Hussain 2017, Wong 1989, see link to HbVar and references therein). This variant is also reported in ClinVar (Variation ID: 36341), and is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical acceptor splice site. Based on available information, this variant is considered to be likely pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Chiou SS et al. Molecular basis and haematological characterization of beta-thalassaemia major in Taiwan, with a mutation of IVS-1 3' end TAG-->GAG in a Chinese patient. Br J Haematol. 1993 Jan;83(1):112-7. PMID: 8435318. Hussain A et al. Rare beta-Globin Gene Mutations in Pakistan. Hemoglobin. 2017 Mar;41(2):100-103. PMID: 28670940. Wong C et al. Beta-thalassemia due to two novel nucleotide substitutions in consensus acceptor splice sequences of the beta-globin gene. Blood. 1989 Mar;73(4):914-8. PMID: 2920213. (less)
|
|
|
Pathogenic
(Mar 01, 1989)
|
no assertion criteria provided
Method: literature only
|
BETA-PLUS-THALASSEMIA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000036980.2
First in ClinVar: Apr 04, 2013 Last updated: May 09, 2018 |
Comment on evidence:
A T-to-G change at position -3 in the acceptor splice site of IVS1 (TAG to GAG) was found in a Saudi Arabian patient with beta-plus-thalassemia … (more)
A T-to-G change at position -3 in the acceptor splice site of IVS1 (TAG to GAG) was found in a Saudi Arabian patient with beta-plus-thalassemia (613985) by Wong et al. (1989). Indeed, Wong et al. (1989) identified 2 different nucleotide substitutions in consensus acceptor splice sequences of the beta-globin gene leading to beta-thalassemia. One was at the IVS1/exon 2 junction and the other at the IVS2/exon 3 junction (141900.0361). Both mutations were single nucleotide substitutions, T-to-G and C-to-A, at position -3 immediately adjacent to the invariant AG dinucleotide. For the IVS2/exon 3 mutation, abnormal splicing into the cryptic splice site at IVS2 nucleotide 579 was demonstrated. (less)
|
|
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Pathogenic
(Nov 25, 2019)
|
no assertion criteria provided
Method: curation
|
beta Thalassemia
Affected status: unknown
Allele origin:
germline
|
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics
Accession: SCV001244584.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
beta Thalassemia
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Genetic Laboratory, Salmaniya Medical Complex
Accession: SCV002073353.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
Indication for testing: Abnormal hemoglobin electrophoresis for premarital counseling of blood genetic disorders
Age: 20-29 years
Sex: male
Comment on evidence:
The patient has a beta-thalassemia complete blood count (CBC) and HPLC profiles (RBC 6.2, MCV 69.6, MCH 22.9, HbA2 4.7%)
|
|
|
Pathogenic
(Mar 25, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Beta thalassemia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002089235.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
The variant found in at least one symptomatic individual. The variant is predicted to negatively affect a known splice site. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and several have a phenotype known to be consistent with disease.
Comment:
The HBB: c.93-3T>G variant (also known as IVS-I-128 (T->G), rs34527846, HbVar ID: 829) is reported in the compound heterozygous state in individuals with beta (+) thalassemia (Chiou 1993, Hussain 2017, Wong 1989, see link to HbVar and references therein). This variant is also reported in ClinVar (Variation ID: 36341), and is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical acceptor splice site. Based on available information, this variant is considered to be likely pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Chiou SS et al. Molecular basis and haematological characterization of beta-thalassaemia major in Taiwan, with a mutation of IVS-1 3' end TAG-->GAG in a Chinese patient. Br J Haematol. 1993 Jan;83(1):112-7. PMID: 8435318. Hussain A et al. Rare beta-Globin Gene Mutations in Pakistan. Hemoglobin. 2017 Mar;41(2):100-103. PMID: 28670940. Wong C et al. Beta-thalassemia due to two novel nucleotide substitutions in consensus acceptor splice sequences of the beta-globin gene. Blood. 1989 Mar;73(4):914-8. PMID: 2920213.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Variant summary: HBB c.93-3T>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 5' splicing donor site. Three predict the variant weakens the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 252420 control chromosomes. c.93-3T>G has been reported in the literature in multiple individuals affected with Beta Thalassemia Intermedia (example, Wong_1989, Chiou_1993, Ho_1998, Sinha_2009, Al-Allawi_2014, Hassan_2015, Hussain_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The The ITHANET community portal has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The variant found in at least one symptomatic individual. The variant is predicted to negatively affect a known splice site. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and several have a phenotype known to be consistent with disease.
Comment:
The HBB: c.93-3T>G variant (also known as IVS-I-128 (T->G), rs34527846, HbVar ID: 829) is reported in the compound heterozygous state in individuals with beta (+) thalassemia (Chiou 1993, Hussain 2017, Wong 1989, see link to HbVar and references therein). This variant is also reported in ClinVar (Variation ID: 36341), and is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical acceptor splice site. Based on available information, this variant is considered to be likely pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Chiou SS et al. Molecular basis and haematological characterization of beta-thalassaemia major in Taiwan, with a mutation of IVS-1 3' end TAG-->GAG in a Chinese patient. Br J Haematol. 1993 Jan;83(1):112-7. PMID: 8435318. Hussain A et al. Rare beta-Globin Gene Mutations in Pakistan. Hemoglobin. 2017 Mar;41(2):100-103. PMID: 28670940. Wong C et al. Beta-thalassemia due to two novel nucleotide substitutions in consensus acceptor splice sequences of the beta-globin gene. Blood. 1989 Mar;73(4):914-8. PMID: 2920213.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Rare β-Globin Gene Mutations in Pakistan. | Hussain A | Hemoglobin | 2017 | PMID: 28670940 |
| Repository of mutations from Oman: The entry point to a national mutation database. | Rajab A | F1000Research | 2015 | PMID: 26594346 |
| Broader spectrum of β-thalassemia mutations in Oman: regional distribution and comparison with neighboring countries. | Hassan SM | Hemoglobin | 2015 | PMID: 25677748 |
| β -thalassemia intermedia in Northern Iraq: a single center experience. | Al-Allawi NA | BioMed research international | 2014 | PMID: 24719849 |
| The spectrum of β-thalassemia mutations in Kermanshah Province in West Iran and its association with hematological parameters. | Mehrabi M | Hemoglobin | 2013 | PMID: 23915319 |
| Influence of BCL11A, HBS1L-MYB, HBBP1 single nucleotide polymorphisms and the HBG2 XmnI polymorphism On Hb F levels. | Roy P | Hemoglobin | 2012 | PMID: 23094636 |
| Invasive & non-invasive approaches for prenatal diagnosis of haemoglobinopathies: experiences from India. | Colah RB | The Indian journal of medical research | 2011 | PMID: 22089620 |
| ThalassoChip, an array mutation and single nucleotide polymorphism detection tool for the diagnosis of β-thalassaemia. | Shammas C | Clinical chemistry and laboratory medicine | 2010 | PMID: 20704537 |
| Profiling β-thalassaemia mutations in India at state and regional levels: implications for genetic education, screening and counselling programmes. | Sinha S | The HUGO journal | 2009 | PMID: 21119755 |
| Regional heterogeneity of beta-thalassemia mutations in the multi ethnic Indian population. | Colah R | Blood cells, molecules & diseases | 2009 | PMID: 19254853 |
| Beta-thalassemia mutations in western India. | Sheth JJ | Indian journal of pediatrics | 2008 | PMID: 18759082 |
| Rare and unexpected mutations among Iranian beta-thalassemia patients and prenatal samples discovered by reverse-hybridization and DNA sequencing. | Najmabadi H | Haematologica | 2002 | PMID: 12368169 |
| Beta-thalassaemia intermedia: is it possible consistently to predict phenotype from genotype? | Ho PJ | British journal of haematology | 1998 | PMID: 9450794 |
| The molecular basis of beta thalassaemia in Punjabi and Maharashtran Indians includes a multilocus aetiology involving triplicated alpha-globin loci. | Garewal G | British journal of haematology | 1994 | PMID: 8199027 |
| Molecular basis and haematological characterization of beta-thalassaemia major in Taiwan, with a mutation of IVS-1 3' end TAG-->GAG in a Chinese patient. | Chiou SS | British journal of haematology | 1993 | PMID: 8435318 |
| Beta-thalassemia due to two novel nucleotide substitutions in consensus acceptor splice sequences of the beta-globin gene. | Wong C | Blood | 1989 | PMID: 2920213 |
| https://ithanet.eu/db/ithagenes?ithaID=115 | - | - | - | - |
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Text-mined citations for rs34527846 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.