rs2227934

Positions:

• chr15-90803693-C-A
• chr15-90803693-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000057.4(BLM):​c.3531C>A​(p.Ala1177Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,613,558 control chromosomes in the GnomAD database, including 23,763 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1904 hom., cov: 32)
  • Exomes 𝑓: 0.17 (21859 hom.)
• Consequence: BLM NM_000057.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.00

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]

BLM (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 15-90803693-C-A is Benign according to our data. Variant chr15-90803693-C-A is described in ClinVar as [Benign]. Clinvar id is 92395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-90803693-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BLM	NM_000057.4	c.3531C>A	p.Ala1177Ala	synonymous_variant	18/22	ENST00000355112.8	NP_000048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BLM	ENST00000355112.8	c.3531C>A	p.Ala1177Ala	synonymous_variant	18/22	1	NM_000057.4	ENSP00000347232.3

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23353 AN: 151944 Hom.: 1907 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.0925

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.149

GnomAD3 exomes AF: 0.151 AC: 38074 AN: 251328 Hom.: 3104 AF XY: 0.150 AC XY: 20440 AN XY: 135848

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.0884

Gnomad ASJ exome AF: 0.166

Gnomad EAS exome AF: 0.180

Gnomad SAS exome AF: 0.0888

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.187

Gnomad OTH exome AF: 0.156

GnomAD4 exome AF: 0.170 AC: 248242 AN: 1461496 Hom.: 21859 Cov.: 33 AF XY: 0.168 AC XY: 122051 AN XY: 727062

Gnomad4 AFR exome AF: 0.117

Gnomad4 AMR exome AF: 0.0935

Gnomad4 ASJ exome AF: 0.165

Gnomad4 EAS exome AF: 0.177

Gnomad4 SAS exome AF: 0.0891

Gnomad4 FIN exome AF: 0.147

Gnomad4 NFE exome AF: 0.182

Gnomad4 OTH exome AF: 0.163

GnomAD4 genome AF: 0.154 AC: 23361 AN: 152062 Hom.: 1904 Cov.: 32 AF XY: 0.150 AC XY: 11157 AN XY: 74322

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.111

Gnomad4 ASJ AF: 0.171

Gnomad4 EAS AF: 0.179

Gnomad4 SAS AF: 0.0934

Gnomad4 FIN AF: 0.146

Gnomad4 NFE AF: 0.187

Gnomad4 OTH AF: 0.149

Alfa AF: 0.172 Hom.: 2992

Bravo AF: 0.149

Asia WGS AF: 0.136 AC: 474 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bloom syndrome Benign:6

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 17, 2023	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 28, 2017	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 29, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

BLM-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 15, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	3.0
DANN	Benign	0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2227934; hg19: chr15-91346923; COSMIC: COSV61922667;