chr15-90769196-C-T
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting
The NM_000057.4(BLM):c.2371C>T(p.Arg791Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000868 in 1,613,678 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000089 ( 0 hom. )
Consequence
BLM
NM_000057.4 missense
NM_000057.4 missense
Scores
6
8
5
Clinical Significance
Conservation
PhyloP100: 4.85
Genes affected
BLM (HGNC:1058): (BLM RecQ like helicase) The Bloom syndrome is an autosomal recessive disorder characterized by growth deficiency, microcephaly and immunodeficiency among others. It is caused by homozygous or compound heterozygous mutation in the gene encoding DNA helicase RecQ protein on chromosome 15q26. This Bloom-associated helicase unwinds a variety of DNA substrates including Holliday junction, and is involved in several pathways contributing to the maintenance of genome stability. Identification of pathogenic Bloom variants is required for heterozygote testing in at-risk families. [provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000657 (10/152280) while in subpopulation EAS AF= 0.00154 (8/5182). AF 95% confidence interval is 0.000768. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152162Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000131 AC: 33AN: 251468Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135906
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GnomAD4 exome AF: 0.0000890 AC: 130AN: 1461398Hom.: 0 Cov.: 32 AF XY: 0.0000922 AC XY: 67AN XY: 727014
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GnomAD4 genome AF: 0.0000657 AC: 10AN: 152280Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74442
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:9Benign:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Bloom syndrome Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | Pars Genome Lab | May 18, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 13, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 02, 2025 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 791 of the BLM protein (p.Arg791Cys). This variant is present in population databases (rs55880859, gnomAD 0.1%). 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: 133698). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BLM protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects BLM function (PMID: 23129629, 24816114, 26788541). 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 15, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 12, 2021 | - - |
not specified Uncertain:1Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 23, 2018 | Variant summary: BLM c.2371C>T (p.Arg791Cys) results in a non-conservative amino acid change located in the Helicase superfamily 1/2, ATP-binding domain and DEAD/DEAH box helicase domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 277226 control chromosomes. This frequency is not higher than expected for a pathogenic variant in BLM causing Bloom Syndrome (0.00012 vs 0.0035), allowing no conclusion about variant significance. The c.2371C>T variant has been reported in the literature in a cancer cell line from a Bloom Syndrome patient. This report does not provide strong evidence about an association of the variant with Bloom Syndrome. Several publications report experimental evidence evaluating an impact on protein function. In one study (Shastri_2015), the variant showed no significant sensitivity to hydroxyurea. However, it showed delayed accumulation and elimination of phosphorylated H2AX upon DNA damage. Moreover, the variant showed a significantly increased level of sister chromatid exchanges compared WT controls. Another study (Mirzaei_2012) described the variant as a partial loss of function via yeast growth assays, and suggested this was due to the variants proximity to an invariant residue (D795), thus causing only a partial loss of ATP hydrolysis activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 08, 2024 | The BLM c.2371C>T (p.Arg791Cys) variant has been reported in the published literature in experimental studies with inconclusive functional evidence. It is noted to result in partial loss of function in yeast based assays (PMID: 23129629 (2012)). Additionally, it is described to destabilize the enzyme and lead to inefficient DNA break repair (PMIDs: 24816114 (2014), 26788541 (2016)). However, it is also noted to show normal cell survival with unclear sensitivity to certain cancer medications (PMID: 26788541 (2016)). Further evidence is needed. To the best of our knowledge, this variant has not been reported in individuals with BLM-associated disease. The frequency of this variant in the general population, 0.0013 (25/19954 chromosomes in East Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Cancer Genomics Group, Japanese Foundation For Cancer Research | May 01, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Uncertain
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at