15-90809232-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000057.4(BLM):c.3847C>T(p.Gln1283Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000616 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q1283Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000057.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BLM | NM_000057.4 | c.3847C>T | p.Gln1283Ter | stop_gained | 20/22 | ENST00000355112.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BLM | ENST00000355112.8 | c.3847C>T | p.Gln1283Ter | stop_gained | 20/22 | 1 | NM_000057.4 | P2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251478Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135910
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727246
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Bloom syndrome Pathogenic:5
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Aug 16, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 16, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 09, 2022 | Variant summary: BLM c.3847C>T (p.Gln1283X) 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 251478 control chromosomes. c.3847C>T has been reported in the literature as a homozygous genotype in at-least one in individual affected with Bloom Syndrome (example, German_2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 16, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 12, 2023 | This sequence change creates a premature translational stop signal (p.Gln1283*) 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 (rs367543031, gnomAD 0.003%). 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: 42089). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 28, 2022 | The p.Q1283* pathogenic mutation (also known as c.3847C>T), located in coding exon 19 of the BLM gene, results from a C to T substitution at nucleotide position 3847. This changes the amino acid from a glutamine to a stop codon within coding exon 19. This variant was reported in a homozygous state in 1/134 patients from a Bloom syndrome registry (German J et al. Hum. Mutat. 2007 Aug;28:743-53). In a pan-ethnic population screen for Bloom syndrome carrier status, this variant was reported in 3/22864 individuals (Perreault-Micale C et al. Mol Genet Genomic Med. 2015 Jul;3:363-73). 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