ClinVar Genomic variation as it relates to human health
NM_000057.4(BLM):c.3044C>T (p.Thr1015Ile)
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_000057.4(BLM):c.3044C>T (p.Thr1015Ile)
Variation ID: 127494 Accession: VCV000127494.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q26.1 15: 90794191 (GRCh38) [ NCBI UCSC ] 15: 91337421 (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 Feb 24, 2015 May 1, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000057.4:c.3044C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000048.1:p.Thr1015Ile missense NM_001287246.2:c.3044C>T NP_001274175.1:p.Thr1015Ile missense NM_001287247.2:c.3044C>T NP_001274176.1:p.Thr1015Ile missense NM_001287248.2:c.1919C>T NP_001274177.1:p.Thr640Ile missense NC_000015.10:g.90794191C>T NC_000015.9:g.91337421C>T NG_007272.1:g.81820C>T LRG_20:g.81820C>T LRG_20t1:c.3044C>T - Protein change
- T1015I, T640I
- Other names
- p.T1015I:ACA>ATA
- Canonical SPDI
- NC_000015.10:90794190:C: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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0.00020 (G)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00009
The Genome Aggregation Database (gnomAD) 0.00013
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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BLM | - | - |
GRCh38 GRCh37 |
4287 | 4338 |
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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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 3, 2021 | RCV000115302.5 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV000473191.15 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Aug 2, 2023 | RCV000570913.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 23, 2022 | RCV001824609.2 |
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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Uncertain significance
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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Bloom syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000543349.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1015 of the BLM protein (p.Thr1015Ile). … (more)
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1015 of the BLM protein (p.Thr1015Ile). This variant is present in population databases (rs202196488, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with BLM-related conditions. ClinVar contains an entry for this variant (Variation ID: 127494). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BLM protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Aug 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000672908.6
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.T1015I variant (also known as c.3044C>T), located in coding exon 15 of the BLM gene, results from a C to T substitution at nucleotide … (more)
The p.T1015I variant (also known as c.3044C>T), located in coding exon 15 of the BLM gene, results from a C to T substitution at nucleotide position 3044. The threonine at codon 1015 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Jan 27, 2014)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000149211.10
First in ClinVar: May 17, 2014 Last updated: Feb 24, 2015 |
Comment:
Single pathogenic variants in BLM have only recently been described in association with cancer predisposition and the risks are not well understood. This variant is … (more)
Single pathogenic variants in BLM have only recently been described in association with cancer predisposition and the risks are not well understood. This variant is denoted BLM c.3044C>T at the cDNA level, p.Thr1015Ile (T1015I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BLM Thr1015Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative substitution of a neutral polar amino acid for a neutral non-polar one, altering a position that is well conserved throughout evolution and is located in the Helicase C-terminal domain per UNIPROT and Interpro. Multiple in silico algorithms predict that this variant may be damaging to protein structure and function. On a molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and with single variants in BLM in general, remain unclear. (less)
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Uncertain significance
(Jan 23, 2022)
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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: SCV002074413.1
First in ClinVar: Feb 12, 2022 Last updated: Feb 12, 2022 |
Comment:
Variant summary: BLM c.3044C>T (p.Thr1015Ile) results in a non-conservative amino acid change located in the ATP-dependent DNA helicase RecQ, zinc-binding domain (IPR032284) of the encoded … (more)
Variant summary: BLM c.3044C>T (p.Thr1015Ile) results in a non-conservative amino acid change located in the ATP-dependent DNA helicase RecQ, zinc-binding domain (IPR032284) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 248866 control chromosomes, predominantly at a frequency of 0.00024 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BLM causing Bloom Syndrome (0.00012 vs 0.0035), allowing no conclusion about variant significance. c.3044C>T has been reported in the literature in individuals affected with pediatric cancers (Muskens_2020, Crompton_2014), which is a known component of Bloom Syndrome. These reports do not provide unequivocal conclusions about association of the variant with Bloom Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed the variant since 2014: all submitters classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Jul 27, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002530038.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The BLM c.3044C>T (p.T1015I) variant has not been reported in the literature to our knowledge. It was observed in 33/128234 chromosomes of the European (non-Finnish) … (more)
The BLM c.3044C>T (p.T1015I) variant has not been reported in the literature to our knowledge. It was observed in 33/128234 chromosomes of the European (non-Finnish) subpopulation, with no homozygotes, in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654) and has been reported in ClinVar (Variation ID 127494). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Jan 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Bloom syndrome
Affected status: unknown
Allele origin:
germline
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St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV002525977.2
First in ClinVar: Jun 16, 2022 Last updated: Dec 24, 2022 |
Comment:
The BLM c.3044C>T (p.Thr1015Ile) missense change has a maximum subpopulation frequency of 0.025% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/15-91337421-C-T ). Five of seven in silico tools predict … (more)
The BLM c.3044C>T (p.Thr1015Ile) missense change has a maximum subpopulation frequency of 0.025% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/15-91337421-C-T ). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but these predictions have not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Bloom syndrome. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4. (less)
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Uncertain significance
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010756.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Uncertain significance
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Bloom syndrome
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001454871.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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
HelpText-mined citations for rs202196488 ...
HelpRecord last updated May 08, 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.