15-90763047-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000057.4(BLM):āc.1964T>Cā(p.Met655Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,828 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M655I) has been classified as Uncertain significance.
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.1964T>C | p.Met655Thr | missense_variant | 8/22 | ENST00000355112.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BLM | ENST00000355112.8 | c.1964T>C | p.Met655Thr | missense_variant | 8/22 | 1 | NM_000057.4 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152064Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251184Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135768
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461764Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727184
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152064Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74274
ClinVar
Submissions by phenotype
Bloom syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2022 | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 655 of the BLM protein (p.Met655Thr). This variant is present in population databases (rs748567176, gnomAD 0.01%). 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: 485343). 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. 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. | Sep 02, 2018 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 02, 2024 | The p.M655T variant (also known as c.1964T>C), located in coding exon 7 of the BLM gene, results from a T to C substitution at nucleotide position 1964. The methionine at codon 655 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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