rs1555420842

Positions:

• chr15-90769165-G-GGA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000355112.8(BLM):​c.2343_2344dup​(p.Asn782ArgfsTer34) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000342 in 1,461,330 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L780L) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BLM ENST00000355112.8 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.76

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 18 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 15-90769165-G-GGA is Pathogenic according to our data. Variant chr15-90769165-G-GGA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 405291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BLM	NM_000057.4	c.2343_2344dup	p.Asn782ArgfsTer34	frameshift_variant	11/22	ENST00000355112.8	NP_000048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BLM	ENST00000355112.8	c.2343_2344dup	p.Asn782ArgfsTer34	frameshift_variant	11/22	1	NM_000057.4	ENSP00000347232	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461330 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727014

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bloom syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 08, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 31, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 405291). This variant has not been reported in the literature in individuals affected with BLM-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn782Argfs*34) in the BLM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BLM are known to be pathogenic (PMID: 17407155). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 20, 2017	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2023

The c.2343_2344dupGA pathogenic mutation, located in coding exon 10 of the BLM gene, results from a duplication of GA at nucleotide position 2343, causing a translational frameshift with a predicted alternate stop codon (p.N782Rfs*34). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is interpreted as a disease-causing mutation. -

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: rs1555420842; hg19: chr15-91312395;