rs367543012
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PM2PP3_ModeratePP5_Very_Strong
The NM_000057.4(BLM):c.2407dup(p.Trp803LeufsTer4) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,828 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q802Q) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000057.4 frameshift, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BLM | NM_000057.4 | c.2407dup | p.Trp803LeufsTer4 | frameshift_variant, splice_region_variant | ENST00000355112.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BLM | ENST00000355112.8 | c.2407dup | p.Trp803LeufsTer4 | frameshift_variant, splice_region_variant | 1 | NM_000057.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251410Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135882
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461828Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727206
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Bloom syndrome Pathogenic:4Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 28, 2019 | Variant summary: BLM c.2407dupT (p.Trp803LeufsX4) 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 251410 control chromosomes (gnomAD). c.2407dupT has been reported in the literature in individuals affected with Bloom Syndrome (German_2007). Two ClinVar submitters including a reputable database (Gene Reviews) (evaluation after 2014) cite the variant as pathogenic. Furthermore, Gene Reviews reports the variant as the second most common pathogenic variant for Bloom Syndrome in the Ashkenazi Jewish population (Flanagan_2019). Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 27, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with Bloom syndrome (PMID: 17407155). ClinVar contains an entry for this variant (Variation ID: 42177). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Trp803Leufs*4) 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). - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 22, 2017 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Apr 28, 2015 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 14, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 18, 2017 | The c.2407dupT variant in the BLM gene has been previously reported previously in the heterozygous state in at least two individuals with Bloom syndrome. Information on a second variant in these individuals was not specified (German et al., 2007). This duplication causes a frameshift starting with codon Tryptophan 803, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Trp803LeufsX4. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Based on currently available evidence, we consider c.2407dupT to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at