rs747281324
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000057.4(BLM):c.2015A>G(p.Gln672Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,054 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q672H) has been classified as Uncertain significance.
Frequency
Consequence
NM_000057.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BLM | NM_000057.4 | c.2015A>G | p.Gln672Arg | missense_variant | 8/22 | ENST00000355112.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BLM | ENST00000355112.8 | c.2015A>G | p.Gln672Arg | missense_variant | 8/22 | 1 | NM_000057.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152216Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251340Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135834
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461838Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15AN XY: 727218
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74368
ClinVar
Submissions by phenotype
Bloom syndrome Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 25, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Sep 11, 2014 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 26, 2023 | This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 672 of the BLM protein (p.Gln672Arg). This variant is present in population databases (rs747281324, gnomAD 0.005%). This missense change has been observed in individuals with Bloom syndrome (PMID: 17407155). ClinVar contains an entry for this variant (Variation ID: 188963). 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 expected to disrupt BLM protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects BLM function (PMID: 10069810, 10812332, 12444098, 17878217, 22582397, 31253795). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 22, 2021 | This variant has been reported in individuals with Bloom syndrome in the published literature (PMID: 17407155 (2007) and 7585968 (1995)). Functional studies show that this variant is damaging to protein function (PMID: 31253795 (2019), 22582397 (2012), 17878217 (2007), 12444098 (2002), 10812332 (2000), 10069810 (1999)). Predicted to have a damaging effect on the protein. Based on the available information, this variant is classified as likely pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 17, 2023 | The p.Q672R variant (also known as c.2015A>G), located in coding exon 7 of the BLM gene, results from an A to G substitution at nucleotide position 2015. The glutamine at codon 672 is replaced by arginine, an amino acid with highly similar properties. This alteration was reported in two individuals diagnosed with Bloom syndrome (German J et al. Hum. Mutat. 2007 Aug;28:743-53). Functional studies showed that this alteration has reduces the ATP binding, ATPase and helicase activities of the BLM protein and increases sister chromatid exchange and recombination rates in cells (Guo RB et al. Nucleic Acids Res. 2007 Sep;35:6297-310; Neff NF et al. Mol. Biol. Cell. 1999 Mar;10:665-76; Onoda F et al. Mutat. Res. 2000 Apr;459:203-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at