rs142551229

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_000057.4(BLM):c.2263A>G(p.Lys755Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000235 in 1,602,870 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

BLM
NM_000057.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:9O:1

Conservation

PhyloP100: 5.41

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01152724).

BP6

Variant 15-90766979-A-G is Benign according to our data. Variant chr15-90766979-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 133697.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=2, Uncertain_significance=3, not_provided=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00127 (194/152334) while in subpopulation AFR AF= 0.0045 (187/41574). AF 95% confidence interval is 0.00397. There are 1 homozygotes in gnomad4. There are 88 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLM	NM_000057.4 link	c.2263A>G	p.Lys755Glu	missense_variant	Exon 10 of 22	ENST00000355112.8	NP_000048.1	P54132

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLM	ENST00000355112.8 link	c.2263A>G	p.Lys755Glu	missense_variant	Exon 10 of 22	1	NM_000057.4	ENSP00000347232.3		P54132

Frequencies

GnomAD3 genomes

AF:

0.00127

AC:

194

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00451

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000280

AC:

AN:

249774

Hom.:

AF XY:

0.000207

AC XY:

AN XY:

135056

show subpopulations

Gnomad AFR exome

AF:

0.00418

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000125

AC:

182

AN:

1450536

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

722012

show subpopulations

Gnomad4 AFR exome

AF:

0.00437

Gnomad4 AMR exome

AF:

0.0000897

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000118

Gnomad4 OTH exome

AF:

0.000300

GnomAD4 genome

AF:

0.00127

AC:

194

AN:

152334

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.00450

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000182

Hom.:

Bravo

AF:

0.00166

ESP6500AA

AF:

0.00432

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000338

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:9Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Dec 26, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 27, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest no damaging effect: showed similar effects on hypersensitivity to the DNA-damaging agent hypdroxyuruea as the wild type (Mirzaei 2012); Identified in healthy individuals undergoing whole genome sequencing (Bodian 2014); This variant is associated with the following publications: (PMID: 24728327, 23129629) -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2Other:1

Sep 19, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BLM c.2263A>G (p.Lys755Glu) results in a conservative amino acid change located in the DEAD/DEAH box helicase domain (IPR011545) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 251136 control chromosomes (gnomAD and Bodian_2014), predominantly at a frequency of 0.0042 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in BLM causing Bloom Syndrome phenotype (0.0035), suggesting that the variant may be a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.2263A>G in individuals affected with Bloom Syndrome has been reported. At least one publication reported experimental evidence evaluating an impact of the variant on protein function in a humanized yeast model system treated with a DNA damaging agent (e.g. Mirzaei_2012). The results showed no difference in sensitivity compared to WT, suggesting the variant does not have a damaging effect on the ability of the protein to maintain genome stability. Nine submitters have provided assessments for this variant to ClinVar after 2014 with conflicting assessments (VUS n=4, likely benign n=4, benign n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Jun 20, 2017

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bloom syndrome

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:2

Jan 09, 2022

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Mar 22, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

BLM-related disorder

Benign:1

Apr 08, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary cancer

Benign:1

Jan 23, 2024

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;.

Eigen

Benign

-0.11

Eigen_PC

Benign

0.084

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

N;.

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.1

D;D

REVEL

Benign

0.16

Sift

Benign

0.075

T;T

Sift4G

Uncertain

0.028

D;D

Polyphen

0.071

B;.

Vest4

0.46

MVP

0.68

MPC

0.55

ClinPred

0.055

GERP RS

5.7

Varity_R

0.66

gMVP

0.73

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

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