15-90769593-T-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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:13
• Conservation: PhyloP100: 1.04
• Publications: 29 publications found

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 Gene-Disease associations (from GenCC):

• Bloom syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Orphanet, Genomics England PanelApp, ClinGen
• osteosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 92392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000057.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLM	NM_000057.4	MANE Select	c.2555+7T>C		splice_region intron	N/A	NP_000048.1
	BLM	NM_001287246.2		c.2555+7T>C		splice_region intron	N/A	NP_001274175.1
	BLM	NM_001287247.2		c.2555+7T>C		splice_region intron	N/A	NP_001274176.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLM	ENST00000355112.8	TSL:1 MANE Select	c.2555+7T>C		splice_region intron	N/A	ENSP00000347232.3
	BLM	ENST00000560509.5	TSL:1	c.2555+7T>C		splice_region intron	N/A	ENSP00000454158.1
	BLM	ENST00000559724.5	TSL:1	n.*1479+7T>C		splice_region intron	N/A	ENSP00000453359.1

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

GnomAD2 exomes AF: 0.280 AC: 69977 AN: 250054 AF XY: 0.269

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 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

African (AFR) AF: 0.605 AC: 20218 AN: 33444

American (AMR) AF: 0.238 AC: 10621 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 6087 AN: 26128

East Asian (EAS) AF: 0.313 AC: 12411 AN: 39670

South Asian (SAS) AF: 0.182 AC: 15685 AN: 86222

European-Finnish (FIN) AF: 0.275 AC: 14674 AN: 53394

Middle Eastern (MID) AF: 0.201 AC: 1131 AN: 5636

European-Non Finnish (NFE) AF: 0.281 AC: 312762 AN: 1111086

Other (OTH) AF: 0.288 AC: 17351 AN: 60326

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

African (AFR) AF: 0.582 AC: 24085 AN: 41390

American (AMR) AF: 0.274 AC: 4187 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 784 AN: 3464

East Asian (EAS) AF: 0.316 AC: 1631 AN: 5156

South Asian (SAS) AF: 0.192 AC: 923 AN: 4808

European-Finnish (FIN) AF: 0.273 AC: 2873 AN: 10516

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.286 AC: 19399 AN: 67932

Other (OTH) AF: 0.320 AC: 674 AN: 2108

Alfa AF: 0.308 Hom.: 9045

Bravo AF: 0.370

Asia WGS AF: 0.274 AC: 952 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bloom syndrome Benign:6

Mar 28, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 01, 2021

Genome-Nilou Lab

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

Jul 29, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Hereditary cancer-predisposing syndrome Benign:1

Jul 10, 2025

GeneKor MSA

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	10
DANN	Benign	0.83
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3815003; hg19: chr15-91312823; COSMIC: COSV61923783; COSMIC: COSV61923783;