rs1057516261

chr15-90811326-TGAAAG-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000057.4(BLM):c.4000_4004del(p.Arg1334GlufsTer11) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000342 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BLM NM_000057.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 4.28

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-90811326-TGAAAG-T is Pathogenic according to our data. Variant chr15-90811326-TGAAAG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 370136.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLM	NM_000057.4	c.4000_4004del	p.Arg1334GlufsTer11	frameshift_variant	21/22	ENST00000355112.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLM	ENST00000355112.8	c.4000_4004del	p.Arg1334GlufsTer11	frameshift_variant	21/22	1	NM_000057.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461886 Hom.: 0 AF XY: 0.00000413 AC XY: 3 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Bloom syndrome Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Nov 24, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	This sequence change creates a premature translational stop signal (p.Arg1334Glufs*11) in the BLM gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 84 amino acid(s) of the BLM protein. This variant is not present in population databases (gnomAD no frequency). 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: 370136). This variant disrupts the nuclear localization signal (NLS) and the topoisomerase I (TOP1) domain of BLM protein, which are critical for BLM localization to the nucleus and TOP1-mediated RNA:DNA unwinding (PMID: 27657136, 9388480, 10569803). While functional studies have not been performed to directly test the effect of this variant on BLM protein function, this suggests that disruption of this region of the protein is causative of disease. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 16, 2021	- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2023

The c.4000_4004delAGGAA variant, located in coding exon 20 of the BLM gene, results from a deletion of 5 nucleotides at nucleotide positions 4000 to 4004, causing a translational frameshift with a predicted alternate stop codon (p.R1334Efs*11). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of BLM, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 84 amino acids of the protein. This alteration changes amino acid residues within the nuclear localization signal of the BLM protein (Kaneko H et al. Biochem Biophys Res Commun. 1997 Nov 17;240(2):348-53, Gharibyan V and Youssoufian H. Mol Carcinog. 1999 Dec;26(4):261-73) and amino acid residues involved in the interaction of BLM with topoisomerase I (TOP1) (Tangeman L et al. Genes (Basel). 2016 Sep 21;7(9)). However, the exact functional impact of this alteration on BLM activity is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057516261; hg19: chr15-91354556;