rs367543043

Positions:

• chr15-90760908-GA-G
• chr15-90760908-GA-GAA

Variant summary

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

The NM_000057.4(BLM):​c.1544del​(p.Asn515MetfsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000933 in 1,608,492 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G512G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: BLM NM_000057.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.716

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 15-90760908-GA-G is Pathogenic according to our data. Variant chr15-90760908-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 374315.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.1544del	p.Asn515MetfsTer16	frameshift_variant	7/22	ENST00000355112.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLM	ENST00000355112.8	c.1544del	p.Asn515MetfsTer16	frameshift_variant	7/22	1	NM_000057.4	P2

Frequencies

GnomAD3 genomes AF: 0.00000667 AC: 1 AN: 150032 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000960 AC: 14 AN: 1458460 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 725626

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.00000991

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000667 AC: 1 AN: 150032 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73124

Gnomad4 AFR AF: 0.0000245

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bloom syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 30, 2017	Variant summary: The BLM c.1544delA (p.Asn515MetfsX16) variant results in a premature termination codon, predicted to cause a truncated or absent BLM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.2824-1077_3019+310del1583, p.V942fs; c.2207_2212del6insTAGATTC, p.Tyr736fsX5; c.772_773delCT, p.Leu258fsX7). One in silico tool predicts a damaging outcome for this variant.This variant is absent in 245606 control chromosomes (gnomAD). A different variant (BLM c.1544_1545dupA) leading to the same protein change, p.Asn515MetfsX16, was reported in multiple Bloom Syndrome patients (German_2007). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 29, 2023	This sequence change creates a premature translational stop signal (p.Asn515Metfs*16) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with congenital anomalies (PMID: 27959697). ClinVar contains an entry for this variant (Variation ID: 374315). For these reasons, this variant has been classified as Pathogenic. -

BLM-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 09, 2023

The BLM c.1544delA variant is predicted to result in a frameshift and premature protein termination (p.Asn515Metfs*16). This variant was reported in compound heterozygous state in an individual with Bloom syndrome (Deng M et al 2021. PubMed ID: 34177791). Of note, another truncating variant affecting the same amino acid (reported as c.1544_1545dupA, p.Asn515fs) has also been reported to be pathogenic for Bloom syndrome (German J et al 2007. PubMed ID: 17407155). This variant is reported in 0.017% of alleles in individuals of African descent in gnomAD and it is classified as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/374315/). Frameshift variants in BLM are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 19, 2021

The c.1544delA pathogenic mutation, located in coding exon 6 of the BLM gene, results from a deletion of one nucleotide at nucleotide position 1544, causing a translational frameshift with a predicted alternate stop codon (p.N515Mfs*16). This alteration has been detected in trans with a pathogenic BLM variant in an individual with Bloom syndrome (Deng M et al. Front Endocrinol (Lausanne), 2021 Jun;12:524242). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs367543043; hg19: chr15-91304138;