chr15-90794174-AG-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000057.4(BLM):βc.3028delGβ(p.Asp1010MetfsTer24) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000563 in 1,599,500 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000057.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152158Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 248358Hom.: 0 AF XY: 0.00000745 AC XY: 1AN XY: 134304
GnomAD4 exome AF: 0.00000415 AC: 6AN: 1447342Hom.: 0 Cov.: 29 AF XY: 0.00000555 AC XY: 4AN XY: 720406
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152158Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74338
ClinVar
Submissions by phenotype
Bloom syndrome Pathogenic:7
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This sequence change creates a premature translational stop signal (p.Asp1010Metfs*24) 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). This variant is present in population databases (rs780379121, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Bloom syndrome (PMID: 17407155). ClinVar contains an entry for this variant (Variation ID: 189048). For these reasons, this variant has been classified as Pathogenic. -
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Variant summary: BLM c.3028delG (p.Asp1010MetfsX24) 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 1.2e-05 in 248358 control chromosomes (gnomAD). c.3028delG has been reported in the literature in a homozygous and compound heterozygote individuals affected with Bloom Syndrome (German_2007). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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not provided Pathogenic:2
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DNA sequence analysis of the BLM gene demonstrated a single base pair deletion in exon 16, c.3028del. This sequence change results in an amino acid frameshift and creates a premature stop codon 24 amino acids downstream of the change, p.Asp1010Metfs*24. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated BLM protein with potentially abnormal function. This sequence change has been previously described in the homozygous and compound heterozygous states in three individuals with Bloom syndrome (PMID: 17407155). This sequence change has been described in four non-Finnish European individuals in the gnomAD population database (rs780379121). Collectively these evidences suggest that, the c.3028del change is likely pathogenic, however functional studies have not been performed to prove this conclusively. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.3028delG pathogenic mutation, located in coding exon 15 of the BLM gene, results from a deletion of one nucleotide at nucleotide position 3028, causing a translational frameshift with a predicted alternate stop codon (p.D1010Mfs*24). This alteration has been reported in three individuals with Bloom syndrome, one of whom was homozygous for c.3028delG (German J et al. Hum. Mutat. 2007 Aug;28:743-53). This alteration was also identified in a cohort of metastatic prostate cancer patients (Ledet EM et al. Prostate. 2020 02;80:235-237). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at