15-90766984-A-G
Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The NM_000057.4(BLM):āc.2268A>Gā(p.Lys756Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,599,836 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000057.4 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00166 AC: 252AN: 152230Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00187 AC: 466AN: 249810Hom.: 0 AF XY: 0.00205 AC XY: 277AN XY: 135102
GnomAD4 exome AF: 0.00237 AC: 3435AN: 1447488Hom.: 4 Cov.: 29 AF XY: 0.00242 AC XY: 1747AN XY: 720666
GnomAD4 genome AF: 0.00165 AC: 252AN: 152348Hom.: 1 Cov.: 32 AF XY: 0.00141 AC XY: 105AN XY: 74508
ClinVar
Submissions by phenotype
Bloom syndrome Uncertain:1Benign:3
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not specified Benign:4
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This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Variant summary: BLM c.2268A>G alters a non-conserved nucleotide resulting in a synonymous change. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0023 in 1599836 control chromosomes, predominantly at a frequency of 0.004 within the South Asian subpopulation in the gnomAD database (gnomAD v4.1.0). The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.13 fold of the estimated maximal expected allele frequency for a pathogenic variant in BLM causing Bloom Syndrome phenotype (0.0035). c.2268A>G has been reported in the literature in at least an individual from families with an accumulation of colorectal cancers or with only one sporadic case of very early onset colorectal cancer (example: Djursby_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Bloom Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 33193653). ClinVar contains an entry for this variant (Variation ID: 136514). Based on the evidence outlined above, the variant was classified as benign. -
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not provided Benign:4
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BLM: BP4, BP7 -
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Hereditary cancer-predisposing syndrome Benign:2
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at