15-90761095-A-G

Position:

• chr15-90761095-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000355112.8(BLM):​c.1722A>G​(p.Leu574=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00609 in 1,550,562 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. LA574L?) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0045 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (73 hom.)
• Consequence: BLM ENST00000355112.8 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.378

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 15-90761095-A-G is Benign according to our data. Variant chr15-90761095-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 136511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-90761095-A-G is described in Lovd as [Benign]. Variant chr15-90761095-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.378 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00447 (681/152288) while in subpopulation SAS AF= 0.0245 (118/4818). AF 95% confidence interval is 0.0209. There are 5 homozygotes in gnomad4. There are 345 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BLM	NM_000057.4	c.1722A>G	p.Leu574=	synonymous_variant	7/22	ENST00000355112.8	NP_000048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BLM	ENST00000355112.8	c.1722A>G	p.Leu574=	synonymous_variant	7/22	1	NM_000057.4	ENSP00000347232	P2

Frequencies

GnomAD3 genomes AF: 0.00447 AC: 680 AN: 152170 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0243

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00585

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00631 AC: 1244 AN: 196992 Hom.: 16 AF XY: 0.00716 AC XY: 752 AN XY: 105042

Gnomad AFR exome AF: 0.000966

Gnomad AMR exome AF: 0.00196

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.0000618

Gnomad SAS exome AF: 0.0257

Gnomad FIN exome AF: 0.00450

Gnomad NFE exome AF: 0.00581

Gnomad OTH exome AF: 0.00547

GnomAD4 exome AF: 0.00627 AC: 8769 AN: 1398274 Hom.: 73 Cov.: 31 AF XY: 0.00679 AC XY: 4687 AN XY: 690048

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.00193

Gnomad4 ASJ exome AF: 0.00922

Gnomad4 EAS exome AF: 0.0000509

Gnomad4 SAS exome AF: 0.0244

Gnomad4 FIN exome AF: 0.00488

Gnomad4 NFE exome AF: 0.00556

Gnomad4 OTH exome AF: 0.00594

GnomAD4 genome AF: 0.00447 AC: 681 AN: 152288 Hom.: 5 Cov.: 32 AF XY: 0.00463 AC XY: 345 AN XY: 74470

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0245

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.00585

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00499 Hom.: 3

Bravo AF: 0.00360

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bloom syndrome Benign:6

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 13, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 14, 2023	- -
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	Genome-Nilou Lab	Jul 01, 2021	- -

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 25, 2017	Variant summary: The c.1722A>G (p.Leu574=) in BLM gene is a synonymous change that involves a non-conserved nucleotide. 3/5 programs in Alamut predict that this variant does not affect splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in control dataset of gnomAD at a frequency of 0.0062 (1384/223222 chrs tested, including 16 homozygotes), predominantly in individuals of South Asian descent (0.026; 475/18298 chrs). These frequencies exceed the estimated maximum allele frequency for a pathogenic allele in this gene (0.0035). The variant of interest has been reported as a polymorphism via published reports (German_2007), and is cited as Benign by a reputable databases/clinical laboratories. Taking together, the variant was classified as Benign. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 12, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 06, 2021	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

BLM-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 27, 2019

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2016

This alteration is classified as likely 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	-0.82
CADD	Benign	6.9
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs28385011; hg19: chr15-91304325; COSMIC: COSV61924631; COSMIC: COSV61924631;