rs587778105
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2PM4_SupportingBP6BS1
The NM_000057.4(BLM):c.387_389del(p.Lys130del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,614,072 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00014 ( 1 hom. )
Consequence
BLM
NM_000057.4 inframe_deletion
NM_000057.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.08
Genes affected
BLM (HGNC:1058): (BLM RecQ like helicase) The Bloom syndrome is an autosomal recessive disorder characterized by growth deficiency, microcephaly and immunodeficiency among others. It is caused by homozygous or compound heterozygous mutation in the gene encoding DNA helicase RecQ protein on chromosome 15q26. This Bloom-associated helicase unwinds a variety of DNA substrates including Holliday junction, and is involved in several pathways contributing to the maintenance of genome stability. Identification of pathogenic Bloom variants is required for heterozygote testing in at-risk families. [provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_000057.4. Strenght limited to Supporting due to length of the change: 1aa.
BP6
?
Variant 15-90749652-AAAG-A is Benign according to our data. Variant chr15-90749652-AAAG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 421741.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3, not_provided=1}.
BS1
?
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000141 (206/1461856) while in subpopulation SAS AF= 0.00234 (202/86256). AF 95% confidence interval is 0.00208. There are 1 homozygotes in gnomad4_exome. There are 147 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BLM | NM_000057.4 | c.387_389del | p.Lys130del | inframe_deletion | 3/22 | ENST00000355112.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BLM | ENST00000355112.8 | c.387_389del | p.Lys130del | inframe_deletion | 3/22 | 1 | NM_000057.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152216Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000283 AC: 71AN: 251276Hom.: 0 AF XY: 0.000353 AC XY: 48AN XY: 135844
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GnomAD4 exome AF: 0.000141 AC: 206AN: 1461856Hom.: 1 AF XY: 0.000202 AC XY: 147AN XY: 727228
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74368
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 29, 2016 | The c.387_389delGAA variant in the BLM gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.387_389delGAA variant results in an in-frame, 3 base pair deletion and results in the loss of the glutamic acid residue at position 130 in the protein, denoted as p.Lys130del. In-frame deletions frequently impact the resultant protein as missense changes do. The c.387_389delGAA variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, the Exome Aggregation Consortium reports c.387_389delGAA was observed in 36/16508 (0.2%) alleles from individuals of South Asian ancestry, but no homozygous individuals were reported in this cohort. Therefore, we interpret c.387_389delGAA as a variant of uncertain significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 10, 2023 | - - |
not specified Uncertain:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 23, 2021 | DNA sequence analysis of the BLM gene demonstrated a 3 base pair deletion in exon 3, c.387_389del. This in-frame deletion is predicted to result in the deletion of a lysine amino acid residue, p.Lys130del. This in-frame sequence change has been described in gnomAD with a low population frequency of 0.028% (rs587778105). This sequence change does not appear to have been previously described in patients with BLM-related disorders and has also not been described as a known benign sequence change in the BLM gene. The functional significance of this sequence change is not known at present and its contribution to this patient's disease phenotype cannot definitively be determined. - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Bloom syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 08, 2021 | 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. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at