rs1057517030
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000057.4(BLM):c.1083_1084delTG(p.Cys361fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,461,566 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
BLM
NM_000057.4 frameshift
NM_000057.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.482
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 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-90754931-CTG-C is Pathogenic according to our data. Variant chr15-90754931-CTG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BLM | NM_000057.4 | c.1083_1084delTG | p.Cys361fs | frameshift_variant | 5/22 | ENST00000355112.8 | NP_000048.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BLM | ENST00000355112.8 | c.1083_1084delTG | p.Cys361fs | frameshift_variant | 5/22 | 1 | NM_000057.4 | ENSP00000347232.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250536Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135436
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GnomAD4 exome AF: 0.0000233 AC: 34AN: 1461566Hom.: 0 AF XY: 0.0000248 AC XY: 18AN XY: 727102
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Bloom syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 03, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 371130). This variant is also known as c.1081_1082delTG. This premature translational stop signal has been observed in individual(s) with colorectal cancer (PMID: 27356891). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Cys361*) in the BLM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BLM are known to be pathogenic (PMID: 17407155). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 06, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 10, 2024 | Variant summary: BLM c.1083_1084delTG (p.Cys361X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 250536 control chromosomes. c.1083_1084delTG has been reported in the literature in one individual affected with familial CRC. 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: 32449991, 27356891). ClinVar contains an entry for this variant (Variation ID: 371130). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 17, 2019 | The c.1083_1084delTG variant, located in coding exon 4 of the BLM gene, results from a deletion of two nucleotides at nucleotide positions 1083 to 1084, causing a translational frameshift with a predicted alternate stop codon (p.C361*). This variant was identified in 1/857 unrelated cases of undefined familial colorectal cancer that were negative for a mutation in a known cancer susceptibility gene for colorectal cancer (CRC) (Dobbins SE et al. Fam. Cancer, 2016 10;15:593-9). This variant was also identified in 1/1006 familial early onset colorectal cancer patients as part of a case-control enrichment analysis that was performed using a publicly available independent cohort of 1006 patients of familial early-onset CRC (CanVar) and the Exome Aggregation Consortium (ExAC) database (Díaz-Gay M et al. Cancers (Basel), 2019 11;3:362). Of note, this alteration is also designated as c.1081_1082delTG in the published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
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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