15-90751918-G-T
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_000057.4(BLM):c.931G>T(p.Ala311Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,612,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A311V) has been classified as Uncertain significance.
Frequency
Consequence
NM_000057.4 missense
Scores
Clinical Significance
Conservation
Publications
- Bloom syndromeInheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Orphanet, Genomics England PanelApp, ClinGen
- osteosarcomaInheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
- breast cancerInheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
- hereditary nonpolyposis colon cancerInheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Likely_benign. The variant received -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152070Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000159 AC: 4AN: 251120 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460414Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726602 show subpopulations
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152070Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74270 show subpopulations
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
The p.A311S variant (also known as c.931G>T), located in coding exon 3 of the BLM gene, results from a G to T substitution at nucleotide position 931. The alanine at codon 311 is replaced by serine, an amino acid with similar properties. This amino acid position is poorly 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. -
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Bloom syndrome Uncertain:1
This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 311 of the BLM protein (p.Ala311Ser). This variant is present in population databases (rs753911420, gnomAD 0.04%). 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: 485358). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BLM protein function with a negative predictive value of 80%. 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. -
not provided Uncertain:1
The BLM c.931G>T (p.Ala311Ser) variant has not been reported in individuals with BLM-related conditions in the published literature. The frequency of this variant in the general population, 0.0004 (4/10078 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at