rs587779886
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Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PM2PP3_ModeratePP5_Very_Strong
The NM_000057.4(BLM):c.3210+2del variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000318 in 1,572,194 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000032 ( 0 hom. )
Consequence
BLM
NM_000057.4 splice_donor
NM_000057.4 splice_donor
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.60
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 Pathogenic. Variant got 20 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.1, offset of -47, new splice context is: tttGTaaga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
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Very rare variant in population databases, with high coverage;
PP3
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Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
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Variant 15-90794358-GT-G is Pathogenic according to our data. Variant chr15-90794358-GT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 127497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-90794358-GT-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BLM | NM_000057.4 | c.3210+2del | splice_donor_variant | ENST00000355112.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BLM | ENST00000355112.8 | c.3210+2del | splice_donor_variant | 1 | NM_000057.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000264 AC: 4AN: 151674Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000463 AC: 1AN: 216206Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 117604
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GnomAD4 exome AF: 0.0000324 AC: 46AN: 1420520Hom.: 0 Cov.: 30 AF XY: 0.0000255 AC XY: 18AN XY: 705470
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GnomAD4 genome ? AF: 0.0000264 AC: 4AN: 151674Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74078
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Bloom syndrome Pathogenic:7
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 16, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 04, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 27, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Feb 13, 2023 | The BLM c.3210+2del intronic change results in the deletion of one nucleotide in intron 16 of the BLM gene. This variant is predicted to result in loss of the native splice donor site and abnormal gene splicing, resulting in nonsense-mediated decay or an abnormal protein product. This variant has been reported in at least one individual with metastatic prostate cancer (PMID: 29439820, 31816118) and in individuals with mesothelioma (PMID: 26556299). It has a maximum subpopulation frequency of 0.0010% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). To our knowledge, this variant has not been reported in individuals with Bloom syndrome. In summary, this variant meets criteria to be classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 03, 2023 | This sequence change affects a splice site in intron 16 of the BLM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs587779886, gnomAD 0.001%). Disruption of this splice site has been observed in individual(s) with mesothelioma (PMID: 26556299, 29439820). ClinVar contains an entry for this variant (Variation ID: 127497). Studies have shown that disruption of this splice site results in skipping of exon 16 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 30, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 20, 2023 | Variant summary: BLM c.3210+2delT is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5 prime splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.6e-06 in 216206 control chromosomes (gnomAD). c.3210+2delT has been reported in the literature in individuals affected with prostate cancer (Antonarakis_2018, Ledet_2020) and mesothelioma (Schrader _2016). In these individuals, a second pathogenic variant has not been reported. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other ClinVar submitters (evaluation after 2014) classify the variant as likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 17, 2023 | The c.3210+2delT intronic variant is located 2 nucleotides after coding exon 15 of the BLM gene. This variant results from a deletion of one nucleotide at position c.3210+2. This variant has been detected in metastatic prostate cancer patients (Antonarakis ES et al. Eur Urol. 2018 Aug;74(2):218-225; Ledet EM et al. Prostate, 2020 02;80:235-237). This variant has also been observed in individuals affected with mesothelioma (Schrader KA et al. JAMA Oncol, 2016 Jan;2:104-11). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -48
DS_DL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at