rs2227933

Positions:

• chr15-90794249-G-A
• chr15-90794249-G-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.3102G>A​(p.Thr1034Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,604,120 control chromosomes in the GnomAD database, including 24,300 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2317 hom., cov: 32)
  • Exomes 𝑓: 0.17 (21983 hom.)
• Consequence: BLM NM_000057.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.60

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=-0.62).
• BP6: Variant 15-90794249-G-A is Benign according to our data. Variant chr15-90794249-G-A is described in ClinVar as [Benign]. Clinvar id is 92394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-90794249-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.6 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.3102G>A	p.Thr1034Thr	synonymous_variant	16/22	ENST00000355112.8	NP_000048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BLM	ENST00000355112.8	c.3102G>A	p.Thr1034Thr	synonymous_variant	16/22	1	NM_000057.4	ENSP00000347232.3

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26159 AN: 151912 Hom.: 2317 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.0969

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.0915

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.162

GnomAD3 exomes AF: 0.156 AC: 38931 AN: 248854 Hom.: 3255 AF XY: 0.154 AC XY: 20725 AN XY: 134480

Gnomad AFR exome AF: 0.188

Gnomad AMR exome AF: 0.0914

Gnomad ASJ exome AF: 0.166

Gnomad EAS exome AF: 0.180

Gnomad SAS exome AF: 0.0882

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.187

Gnomad OTH exome AF: 0.158

GnomAD4 exome AF: 0.171 AC: 248636 AN: 1452090 Hom.: 21983 Cov.: 31 AF XY: 0.169 AC XY: 122093 AN XY: 722340

Gnomad4 AFR exome AF: 0.183

Gnomad4 AMR exome AF: 0.0963

Gnomad4 ASJ exome AF: 0.165

Gnomad4 EAS exome AF: 0.174

Gnomad4 SAS exome AF: 0.0885

Gnomad4 FIN exome AF: 0.147

Gnomad4 NFE exome AF: 0.182

Gnomad4 OTH exome AF: 0.167

GnomAD4 genome AF: 0.172 AC: 26182 AN: 152030 Hom.: 2317 Cov.: 32 AF XY: 0.168 AC XY: 12453 AN XY: 74328

Gnomad4 AFR AF: 0.186

Gnomad4 AMR AF: 0.117

Gnomad4 ASJ AF: 0.171

Gnomad4 EAS AF: 0.178

Gnomad4 SAS AF: 0.0925

Gnomad4 FIN AF: 0.147

Gnomad4 NFE AF: 0.187

Gnomad4 OTH AF: 0.162

Alfa AF: 0.172 Hom.: 3401

Bravo AF: 0.170

Asia WGS AF: 0.139 AC: 484 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bloom syndrome Benign:6

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 17, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not specified Benign:4

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 29, 2013	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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	-0.62
CADD	Benign	4.2
DANN	Benign	0.62
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: rs2227933; hg19: chr15-91337479; COSMIC: COSV61922650;