15-90769593-T-C

Variant names:

• chr15-90769593-T-C
• rs3815003
• NM_000057.4:c.2555+7T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000057.4(BLM):​c.2555+7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 1,612,356 control chromosomes in the GnomAD database, including 72,224 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (11405 hom., cov: 31)
  • Exomes 𝑓: 0.28 (60819 hom.)
• Consequence: BLM NM_000057.4 splice_region, intron
• Scores: Splicing: ADA: 0.001295
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.04

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 15-90769593-T-C is Benign according to our data. Variant chr15-90769593-T-C is described in ClinVar as [Benign]. Clinvar id is 92392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-90769593-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLM	NM_000057.4	c.2555+7T>C		splice_region_variant, intron_variant	Intron 12 of 21	ENST00000355112.8	NP_000048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLM	ENST00000355112.8	c.2555+7T>C		splice_region_variant, intron_variant	Intron 12 of 21	1	NM_000057.4	ENSP00000347232.3

Frequencies

GnomAD3 genomes AF: 0.361 AC: 54735 AN: 151730 Hom.: 11388 Cov.: 31

Gnomad AFR AF: 0.582

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.316

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.273

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.286

Gnomad OTH AF: 0.319

GnomAD3 exomes AF: 0.280 AC: 69977 AN: 250054 Hom.: 10864 AF XY: 0.269 AC XY: 36409 AN XY: 135158

Gnomad AFR exome AF: 0.597

Gnomad AMR exome AF: 0.233

Gnomad ASJ exome AF: 0.235

Gnomad EAS exome AF: 0.316

Gnomad SAS exome AF: 0.179

Gnomad FIN exome AF: 0.271

Gnomad NFE exome AF: 0.277

Gnomad OTH exome AF: 0.264

GnomAD4 exome AF: 0.281 AC: 410940 AN: 1460508 Hom.: 60819 Cov.: 36 AF XY: 0.277 AC XY: 201321 AN XY: 726542

Gnomad4 AFR exome AF: 0.605

Gnomad4 AMR exome AF: 0.238

Gnomad4 ASJ exome AF: 0.233

Gnomad4 EAS exome AF: 0.313

Gnomad4 SAS exome AF: 0.182

Gnomad4 FIN exome AF: 0.275

Gnomad4 NFE exome AF: 0.281

Gnomad4 OTH exome AF: 0.288

GnomAD4 genome AF: 0.361 AC: 54798 AN: 151848 Hom.: 11405 Cov.: 31 AF XY: 0.354 AC XY: 26249 AN XY: 74160

Gnomad4 AFR AF: 0.582

Gnomad4 AMR AF: 0.274

Gnomad4 ASJ AF: 0.226

Gnomad4 EAS AF: 0.316

Gnomad4 SAS AF: 0.192

Gnomad4 FIN AF: 0.273

Gnomad4 NFE AF: 0.286

Gnomad4 OTH AF: 0.320

Alfa AF: 0.306 Hom.: 7206

Bravo AF: 0.370

Asia WGS AF: 0.274 AC: 952 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bloom syndrome Benign:6

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:4

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Jul 29, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	10
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
dbscSNV1_RF	Benign	0.0020
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: rs3815003; hg19: chr15-91312823; COSMIC: COSV61923783; COSMIC: COSV61923783;