rs765061205
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000057.4(BLM):c.959+1_959+9del variant causes a splice donor, splice donor 5th base, coding sequence, intron change. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
BLM
NM_000057.4 splice_donor, splice_donor_5th_base, coding_sequence, intron
NM_000057.4 splice_donor, splice_donor_5th_base, coding_sequence, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.17
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 Pathogenic. Variant got 16 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PP5
?
Variant 15-90751943-TTAGGTAAAC-T is Pathogenic according to our data. Variant chr15-90751943-TTAGGTAAAC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 556630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BLM | NM_000057.4 | c.959+1_959+9del | splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant | 4/22 | ENST00000355112.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BLM | ENST00000355112.8 | c.959+1_959+9del | splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant | 4/22 | 1 | NM_000057.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
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Cov.:
32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250890Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135652
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000275 AC: 4AN: 1456014Hom.: 0 AF XY: 0.00000276 AC XY: 2AN XY: 724618
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Data not reliable, filtered out with message: AS_VQSR
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GnomAD4 genome ? Cov.: 32
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Asia WGS
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Bloom syndrome Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 15, 2022 | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 556630). This variant has not been reported in the literature in individuals affected with BLM-related conditions. This variant is present in population databases (rs765061205, gnomAD 0.007%). This sequence change affects a splice site in intron 4 of the BLM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BLM are known to be pathogenic (PMID: 17407155). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 13, 2018 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 15, 2021 | - - |
Computational scores
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at