ClinVar Genomic variation as it relates to human health
NM_000518.5(HBB):c.316-7C>A
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.
Pathogenic(2); Likely pathogenic(2); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000518.5(HBB):c.316-7C>A
Variation ID: 551906 Accession: VCV000551906.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 5225733 (GRCh38) [ NCBI UCSC ] 11: 5246963 (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 Aug 5, 2018 Mar 30, 2024 Jan 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000518.5:c.316-7C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000011.10:g.5225733G>T NC_000011.9:g.5246963G>T NG_000007.3:g.71883C>A NG_046672.1:g.3668G>T NG_053049.1:g.2054G>T NG_059281.1:g.6339C>A LRG_1232:g.6339C>A LRG_1232t1:c.316-7C>A - Protein change
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- Other names
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IVS-II-844
- Canonical SPDI
- NC_000011.10:5225732:G:T
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00007
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
22 | 1834 | |
LOC107133510 | - | - | - | GRCh38 | - | 1784 |
LOC110006319 | - | - | - | GRCh38 | - | 984 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Likely pathogenic (2) |
criteria provided, single submitter
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May 22, 2017 | RCV000667076.3 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 11, 2024 | RCV001000150.11 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001004563.1 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Aug 7, 2023 | RCV001283996.5 |
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
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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
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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
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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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Likely pathogenic
(May 22, 2017)
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criteria provided, single submitter
Method: clinical testing
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Beta-thalassemia HBB/LCRB
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000791471.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Likely pathogenic
(Sep 27, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001156635.1
First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020 |
Comment:
The c.[316-12T>C; 316-7C>A] complex variant is reported in the literature in multiple individuals as a very mild beta + thalassemia trait (Belisario 2015, Waye 2013), … (more)
The c.[316-12T>C; 316-7C>A] complex variant is reported in the literature in multiple individuals as a very mild beta + thalassemia trait (Belisario 2015, Waye 2013), and has been found in trans with Hb S and Hb C in patients with clinical symptoms (Cross 2007, Belisario 2015, Waye 2013). The c.316-12T>C variant (rs755236703) is only observed on three alleles in the Genome Aggregation Database. The c.316-7C>A variant (rs34483965) is only observed on one allele in the Genome Aggregation Database. These are intronic variants in weakly conserved nucleotides, and computational analyses (Alamut v.2.11) predict that each variant may impact splicing by weakening the nearby canonical acceptor splice site, however, without mRNA analysis it is unclear how the combination of the two variants impact splicing. Based on available information, the c.[316-12T>C; 316-7C>A] complex variant is considered to be likely pathogenic. References: Belisario A et al. Very mild forms of Hb S/beta(+)-thalassemia in Brazilian children. Rev Bras Hematol Hemoter. 2015 37(3):198-201. Cross T et al. Sickle liver disease--an unusual presentation in a compound heterozygote for HbS and a novel beta-thalassemia mutation. Am J Hematol. 2007 82(9):852-4. Waye J et al. Mild beta(+)-thalassemia associated with two linked sequence variants: IVS-II-839 (T>C) and IVS-II-844 (C>A). Hemoglobin. 2013 37(4):378-86. (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: SCV001163647.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
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Uncertain significance
(Feb 09, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001469530.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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Pathogenic
(Aug 07, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003439780.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 551906). This variant is also known as IVS2-844C>A. This variant has been observed in individual(s) with HBB-related conditions (PMID: 17565724, 23651435, 26041423). In some individuals, it has been found in cis (on the same chromosome) with c.316-12T>C. In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change falls in intron 2 of the HBB gene. It does not directly change the encoded amino acid sequence of the HBB protein. (less)
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Uncertain significance
(Jan 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003929037.2
First in ClinVar: Jun 03, 2023 Last updated: Mar 30, 2024 |
Comment:
Variant summary: HBB c.316-7C>A 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.316-7C>A 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. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251142 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.316-7C>A (legacy name IVS-II-844C>A) in isolation has been reported in the literature as a compound heterozygous genotype with the HbS variant in at-least one individual with features of Sickle liver disease (Cross_2007) and as a complex allele in cis with c.316-12T>C (legacy name IVS-II-839T>C) in individuals affected with mild Beta Thalassemia (example, Waye_2013, Belisario_2013). As the possibility of incomplete genotyping in the earlier report (Cross_2007) cannot be entirely excluded, these data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17565724, 23651435, 26041423). ClinVar contains an entry for this variant (Variation ID: 551906). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Likely pathogenic
(Jul 17, 2017)
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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: SCV002089194.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 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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Very mild forms of Hb S/beta(+)-thalassemia in Brazilian children. | Belisário AR | Revista brasileira de hematologia e hemoterapia | 2015 | PMID: 26041423 |
Mild β(+)-thalassemia associated with two linked sequence variants: IVS-II-839 (T>C) and IVS-II-844 (C>A). | Waye JS | Hemoglobin | 2013 | PMID: 23651435 |
The molecular basis of β-thalassemia. | Thein SL | Cold Spring Harbor perspectives in medicine | 2013 | PMID: 23637309 |
Sickle liver disease--an unusual presentation in a compound heterozygote for HbS and a novel beta-thalassemia mutation. | Cross TJ | American journal of hematology | 2007 | PMID: 17565724 |
Factors regulating Hb F synthesis in thalassemic diseases. | Mastropietro F | BMC blood disorders | 2002 | PMID: 11943067 |
Silent thalassemias: genotypes and phenotypes. | Bianco I | Haematologica | 1997 | PMID: 9234571 |
Homozygous beta-thalassaemia resulting in the beta-thalassaemia carrier state phenotype. | Rosatelli MC | British journal of haematology | 1994 | PMID: 7819068 |
Text-mined citations for rs34483965 ...
HelpRecord last updated Sep 29, 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.