rs201770808

Positions:

chr15-90782904-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4BP6

The NM_000057.4(BLM):c.2638G>C(p.Glu880Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000313 in 1,612,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

BLM
NM_000057.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2O:1

Conservation

PhyloP100: 2.65

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26680356).

BP6

Variant 15-90782904-G-C is Benign according to our data. Variant chr15-90782904-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127489.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, not_provided=1, Uncertain_significance=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BLM	NM_000057.4 linkuse as main transcript	c.2638G>C	p.Glu880Gln	missense_variant	13/22	ENST00000355112.8	NP_000048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BLM	ENST00000355112.8 linkuse as main transcript	c.2638G>C	p.Glu880Gln	missense_variant	13/22	1	NM_000057.4	ENSP00000347232	P2

Frequencies

GnomAD3 genomes

AF:

0.0000985

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000220

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000518

AC:

AN:

251176

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135766

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000335

AC:

489

AN:

1460466

Hom.:

Cov.:

AF XY:

0.000289

AC XY:

210

AN XY:

726630

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000432

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000220

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000193

Hom.:

Bravo

AF:

0.000144

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Bloom syndrome

Uncertain:3Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	May 02, 2022	The BLM c.2638G>C (p.Glu880Gln) missense change has a maximum subpopulation frequency of 0.014% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). It has been reported in an individual with colorectal cancer (PMID: 28944238) and in a non-cancer control individual (PMID: 29641532). In silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Bloom syndrome. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 26, 2024	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2014	Single pathogenic variants in BLM have only recently been described in association with cancer predisposition and the risks are not well understood. This variant is denoted BLM c.2638G>C at the cDNA level, p.Glu880Gln (E880Q) at the protein level, and results in the change of a Glutamic Acid to a Glutamine (GAA>CAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BLM Glu880Gln was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. This variant is a semi-conservative substitution in which a negative polar amino acid is replaced with a neutral polar one, altering a position that is well conserved throughout evolution and is located within the Helicase C-terminal domain. In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. On a molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and with single variants the BLM gene in general, remain unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 13, 2022	The frequency of this variant in the general population, 0.00014 (18/129020 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with colorectal cancer (PMID: 28944238 (2017)), but also in a healthy cancer-free individual (PMID: 29641532 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2022

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. -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;.

Eigen

Benign

-0.020

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.86

D;D

M_CAP

Benign

0.0094

MetaRNN

Benign

0.27

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.051

Sift

Benign

0.070

T;D

Sift4G

Benign

0.38

T;T

Polyphen

0.17

B;.

Vest4

0.21

MVP

0.79

MPC

0.10

ClinPred

0.13

GERP RS

4.6

Varity_R

0.25

gMVP

0.55

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