15-90769505-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000057.4(BLM):c.2474C>T(p.Pro825Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000242 in 1,613,792 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P825P) has been classified as Likely benign.
Frequency
Consequence
NM_000057.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BLM | NM_000057.4 | c.2474C>T | p.Pro825Leu | missense_variant | 12/22 | ENST00000355112.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BLM | ENST00000355112.8 | c.2474C>T | p.Pro825Leu | missense_variant | 12/22 | 1 | NM_000057.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152078Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251430Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135896
GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461714Hom.: 0 Cov.: 32 AF XY: 0.0000275 AC XY: 20AN XY: 727156
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152078Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74272
ClinVar
Submissions by phenotype
Bloom syndrome Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 14, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 25, 2022 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 825 of the BLM protein (p.Pro825Leu). This variant is present in population databases (rs749632465, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with BLM-related conditions. ClinVar contains an entry for this variant (Variation ID: 405283). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BLM protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 16, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 05, 2019 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 10, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with primary ovarian insufficiency (Gorsi et al., 2021); This variant is associated with the following publications: (PMID: 32704157, 34718612) - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 06, 2022 | The p.P825L variant (also known as c.2474C>T), located in coding exon 11 of the BLM gene, results from a C to T substitution at nucleotide position 2474. The proline at codon 825 is replaced by leucine, an amino acid with similar properties. In one study, this alteration was detected in 1/1231 colorectal cancer patients and 0/93 controls (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at