15-90811410-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000057.4(BLM):c.4076+4T>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00451 in 1,613,300 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0044 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0045 ( 33 hom. )

Consequence

BLM
NM_000057.4 splice_donor_region, intron

Scores

Splicing: ADA: 0.00003625

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: -0.769

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 15-90811410-T-G is Benign according to our data. Variant chr15-90811410-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 136520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-90811410-T-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00444 (677/152312) while in subpopulation AMR AF= 0.00732 (112/15302). AF 95% confidence interval is 0.00622. There are 5 homozygotes in gnomad4. There are 342 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLM	NM_000057.4 linkuse as main transcript	c.4076+4T>G		splice_donor_region_variant, intron_variant		ENST00000355112.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLM	ENST00000355112.8 linkuse as main transcript	c.4076+4T>G		splice_donor_region_variant, intron_variant		1	NM_000057.4	P2

Frequencies

GnomAD3 genomes

AF:

0.00445

AC:

677

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00733

Gnomad ASJ

AF:

0.0360

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00754

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.00406

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.00443

AC:

1112

AN:

250928

Hom.:

AF XY:

0.00471

AC XY:

640

AN XY:

135760

show subpopulations

Gnomad AFR exome

AF:

0.000555

Gnomad AMR exome

AF:

0.00327

Gnomad ASJ exome

AF:

0.0330

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00274

Gnomad FIN exome

AF:

0.00472

Gnomad NFE exome

AF:

0.00380

Gnomad OTH exome

AF:

0.00668

GnomAD4 exome

AF:

0.00452

AC:

6604

AN:

1460988

Hom.:

Cov.:

AF XY:

0.00463

AC XY:

3362

AN XY:

726850

show subpopulations

Gnomad4 AFR exome

AF:

0.00167

Gnomad4 AMR exome

AF:

0.00356

Gnomad4 ASJ exome

AF:

0.0331

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00266

Gnomad4 FIN exome

AF:

0.00375

Gnomad4 NFE exome

AF:

0.00405

Gnomad4 OTH exome

AF:

0.00742

GnomAD4 genome

AF:

0.00444

AC:

677

AN:

152312

Hom.:

Cov.:

AF XY:

0.00459

AC XY:

342

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000794

Gnomad4 AMR

AF:

0.00732

Gnomad4 ASJ

AF:

0.0360

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00754

Gnomad4 NFE

AF:

0.00406

Gnomad4 OTH

AF:

0.00992

Alfa

AF:

0.00481

Hom.:

Bravo

AF:

0.00483

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.00600

EpiControl

AF:

0.00581

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bloom syndrome

Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 15, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 02, 2018	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	BLM: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 12, 2016	Variant summary: The c.4076+4T>G in a BLM gene is an intronic variant that alters a non-conserved nucleotide. 5/5 in silico tools via Alamut predict this variant to not affect normal splicing, however these predictions have yet to be confirmed by functional assay. The variant is present in control dataset of ExAC at a frequency of 0.0038 (458/119942 chrs tested, including 3 homozygous occurrences) which exceeds the estimated maximum allele frequency for a pathogenic allele in this gene (0.0035), suggesting that this variant is a likely polymorphism. The variant has been reported in affected with breast cancer in literature (Thompson_2012) without strong evidence of causality. Multiple clinical laboratories have classified the variant as "Benign. Taken together, the variant is classified as Benign. -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 28, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 09, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 21, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 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. -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 16, 2018	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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 20, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -

BLM-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 05, 2020

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

Cadd

Benign

2.3

Dann

Benign

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000036

dbscSNV1_RF

Benign

0.018

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over