ClinVar Genomic variation as it relates to human health
NM_000518.5(HBB):c.*110T>C
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000518.5(HBB):c.*110T>C
Variation ID: 36332 Accession: VCV000036332.109
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 5225488 (GRCh38) [ NCBI UCSC ] 11: 5246718 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Dec 12, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000518.5:c.*110T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
3 prime UTR NC_000011.10:g.5225488A>G NC_000011.9:g.5246718A>G NG_000007.3:g.72128T>C NG_046672.1:g.3423A>G NG_053049.1:g.1809A>G NG_059281.1:g.6584T>C LRG_1232:g.6584T>C LRG_1232t1:c.*110T>C - Protein change
- Other names
- AACAAA
- 3-UNT, T-C, +3
- Canonical SPDI
- NC_000011.10:5225487:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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0.00020 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00010
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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 | ||
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HI score
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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. |
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HBB | - | - |
GRCh38 GRCh37 |
21 | 1815 | |
LOC107133510 | - | - | - | GRCh38 | - | 1765 |
LOC110006319 | - | - | - | GRCh38 | - | 975 |
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. |
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Pathogenic (1) |
no assertion criteria provided
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Feb 1, 1985 | RCV000016730.36 | |
Pathogenic (4) |
criteria provided, single submitter
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Mar 5, 2020 | RCV000445649.15 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Dec 12, 2023 | RCV000506540.27 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001004557.9 |
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. |
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Pathogenic
(Jun 30, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601229.2
First in ClinVar: Sep 30, 2017 Last updated: Jan 01, 2022 |
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Pathogenic
(Dec 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000946427.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This variant occurs in a non-coding region of the HBB gene. It does not change the encoded amino acid sequence of the HBB protein. RNA … (more)
This variant occurs in a non-coding region of the HBB gene. It does not change the encoded amino acid sequence of the HBB protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of multiple amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs33978907, gnomAD 0.03%). This variant has been observed in individuals with beta-thalassemia (PMID: 1787101, 4018033, 22335963, 22690826, 23590658). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36332). Studies have shown that this variant results in the activation of a cryptic splice site in 3' UTR (PMID: 4018033). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Hb SS disease
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001163639.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
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Pathogenic
(Mar 05, 2020)
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criteria provided, single submitter
Method: clinical testing
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beta Thalassemia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001338948.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: HBB c.*110T>C is located in the 3UTR downstream of the termination codon involves the alteration of a conserved nucleotide. The variant of interest … (more)
Variant summary: HBB c.*110T>C is located in the 3UTR downstream of the termination codon involves the alteration of a conserved nucleotide. The variant of interest is located within the known "polyA' tail, thus expected to alter mRNA expression, which is supported by Orkin_1985 functional findings. The variant allele was found at a frequency of 6.4e-05 in 31396 control chromosomes (gnomAD), which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.011). c.*110T>C has been reported in the literature in multiple individuals affected with Beta Thalassemia and implicated to be the third most common allele in India (Orkin_1985, Sinha_2009, Italia_2012). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (4x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jun 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV003929400.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
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Pathogenic
(Sep 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000603914.8
First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024 |
Comment:
The HBB c.*110T>C variant (rs33978907, HbVar ID: 968), also known as Poly A (T->C), has been reported in multiple patients diagnosed with beta (+) thalassemia, … (more)
The HBB c.*110T>C variant (rs33978907, HbVar ID: 968), also known as Poly A (T->C), has been reported in multiple patients diagnosed with beta (+) thalassemia, and has been found in a homozygous state, or in-trans with other pathogenic variants (Hoppe 2013, Italia 2012, Orkin 1985, Sinha 2009, Sivalingam 2012, see link to HbVar). Functional characterization of the variant indicates the loss of the canonical polyadenylation site, resulting in an elongated HBB transcript that is less efficiently processed by a downstream cryptic polyadenylation site (Orkin 1985). This variant is listed as pathogenic by multiple laboratories in ClinVar (Variation ID: 36332), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant is located in a conserved region of the 3' UTR, and computational algorithms (Poly A miner) predict an impact on the transcript, consistent with observations from the functional study. Based on available information, the c.*110T>C variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Hoppe CC. Prenatal and newborn screening for hemoglobinopathies. Int J Lab Hematol. 2013 Jun;35(3):297-305. PMID: 23590658. Italia K et al. Variable haematological and clinical presentation of beta-thalassaemia carriers and homozygotes with the Poly A (T?C) mutation in the Indian population. Eur J Haematol. 2012; 89(2):160-4. PMID: 22690826. Orkin S et al. Thalassemia due to a mutation in the cleavage-polyadenylation signal of the human beta-globin gene. EMBO J. 1985; 4(2):453-6. PMID: 4018033. Sinha S et al. Profiling beta-thalassaemia mutations in India at state and regional levels: implications for genetic education, screening and counselling programmes. Hugo J. 2009 Dec;3(1-4):51-62. PMID: 21119755. Sivalingam M et al. Molecular study and genotype/phenotype correlation of beta thalassemia in Malaysia. Int J Lab Hematol. 2012 Aug;34(4):377-82. PMID: 22335963. (less)
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Pathogenic
(Feb 01, 1985)
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no assertion criteria provided
Method: literature only
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BETA-PLUS-THALASSEMIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000037000.2
First in ClinVar: Apr 04, 2013 Last updated: May 09, 2018 |
Comment on evidence:
In an American black patient with beta-plus-thalassemia (613985), Orkin et al. (1985) found a change from AATAAA to AACAAA in the 3-prime untranslated portion of … (more)
In an American black patient with beta-plus-thalassemia (613985), Orkin et al. (1985) found a change from AATAAA to AACAAA in the 3-prime untranslated portion of the gene. This and several others are RNA cleavage and polyadenylation mutants. (less)
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Pathogenic
(Oct 06, 2020)
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no assertion criteria provided
Method: clinical testing
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Beta thalassemia
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002089181.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Pathogenic
(Nov 16, 2015)
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no assertion criteria provided
Method: clinical testing
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Beta-thalassemia HBB/LCRB
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV001132413.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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not provided
(-)
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no classification provided
Method: literature only
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beta Thalassemia
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000537300.3
First in ClinVar: Mar 23, 2017 Last updated: Oct 01, 2022 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Beta-Thalassemia. | Adam MP | - | 2024 | PMID: 20301599 |
Prenatal and newborn screening for hemoglobinopathies. | Hoppe CC | International journal of laboratory hematology | 2013 | PMID: 23590658 |
Variable haematological and clinical presentation of β-thalassaemia carriers and homozygotes with the Poly A (T→C) mutation in the Indian population. | Italia K | European journal of haematology | 2012 | PMID: 22690826 |
Molecular study and genotype/phenotype correlation of β Thalassemia in Malaysia. | Sivalingam M | International journal of laboratory hematology | 2012 | PMID: 22335963 |
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 |
Analysis of beta globin mutations in the Indian population: presence of rare and novel mutations and region-wise heterogeneity. | Edison ES | Clinical genetics | 2008 | PMID: 18294253 |
A mild thalassemia major resulting from a compound heterozygosity for the IVS-II-1 (G----A) mutation and the rare T----C mutation at the polyadenylation site. | Altay C | Hemoglobin | 1991 | PMID: 1787101 |
Thalassemia due to a mutation in the cleavage-polyadenylation signal of the human beta-globin gene. | Orkin SH | The EMBO journal | 1985 | PMID: 4018033 |
https://globin.bx.psu.edu/hbvar/menu.html | - | - | - | - |
Text-mined citations for rs33978907 ...
HelpRecord last updated Mar 23, 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.