rs367543012

chr15-90769437-G-GT

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000057.4(BLM):c.2407dup(p.Trp803LeufsTer4) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q802Q) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BLM NM_000057.4 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 7.80

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 20 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 15-90769437-G-GT is Pathogenic according to our data. Variant chr15-90769437-G-GT is described in ClinVar as [Pathogenic]. Clinvar id is 42177.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.2407dup	p.Trp803LeufsTer4	frameshift_variant, splice_region_variant		ENST00000355112.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLM	ENST00000355112.8	c.2407dup	p.Trp803LeufsTer4	frameshift_variant, splice_region_variant		1	NM_000057.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251410 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461828 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727206

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bloom syndrome Pathogenic:4 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 22, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 28, 2019	Variant summary: BLM c.2407dupT (p.Trp803LeufsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 251410 control chromosomes (gnomAD). c.2407dupT has been reported in the literature in individuals affected with Bloom Syndrome (German_2007). Two ClinVar submitters including a reputable database (Gene Reviews) (evaluation after 2014) cite the variant as pathogenic. Furthermore, Gene Reviews reports the variant as the second most common pathogenic variant for Bloom Syndrome in the Ashkenazi Jewish population (Flanagan_2019). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 27, 2021	For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with Bloom syndrome (PMID: 17407155). ClinVar contains an entry for this variant (Variation ID: 42177). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Trp803Leufs*4) 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, no assertion criteria provided	clinical testing	Counsyl	Apr 28, 2015	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 14, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2017	The c.2407dupT variant in the BLM gene has been previously reported previously in the heterozygous state in at least two individuals with Bloom syndrome. Information on a second variant in these individuals was not specified (German et al., 2007). This duplication causes a frameshift starting with codon Tryptophan 803, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Trp803LeufsX4. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Based on currently available evidence, we consider c.2407dupT to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: 0
DS_AL_spliceai		0.99		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs367543012; hg19: chr15-91312667;