rs201458487
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000057.4(BLM):c.1924G>A(p.Glu642Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,613,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E642E) 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 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BLM | NM_000057.4 | c.1924G>A | p.Glu642Lys | missense_variant | 8/22 | ENST00000355112.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BLM | ENST00000355112.8 | c.1924G>A | p.Glu642Lys | missense_variant | 8/22 | 1 | NM_000057.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152142Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000240 AC: 6AN: 250286Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135314
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461268Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 726866
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152142Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74318
ClinVar
Submissions by phenotype
Bloom syndrome Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 24, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 642 of the BLM protein (p.Glu642Lys). This variant is present in population databases (rs201458487, gnomAD 0.03%). 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: 454090). 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 22, 2024 | The p.E642K variant (also known as c.1924G>A), located in coding exon 7 of the BLM gene, results from a G to A substitution at nucleotide position 1924. The glutamic acid at codon 642 is replaced by lysine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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