rs149754073

chr15-90769187-C-Achr15-90769187-C-Gchr15-90769187-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_000057.4(BLM):c.2362C>A(p.Leu788Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000516 in 1,613,836 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L788F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00042 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00053 ( 1 hom. )

Consequence

BLM
NM_000057.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: 3.15

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013631821).

BP6

Variant 15-90769187-C-A is Benign according to our data. Variant chr15-90769187-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127485.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2, Benign=1}. Variant chr15-90769187-C-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLM	NM_000057.4 linkuse as main transcript	c.2362C>A	p.Leu788Ile	missense_variant	11/22	ENST00000355112.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLM	ENST00000355112.8 linkuse as main transcript	c.2362C>A	p.Leu788Ile	missense_variant	11/22	1	NM_000057.4	P2

Frequencies

GnomAD3 genomes

AF:

0.000421

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00340

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000911

AC:

229

AN:

251482

Hom.:

AF XY:

0.000868

AC XY:

118

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.00587

Gnomad NFE exome

AF:

0.000835

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000525

AC:

768

AN:

1461640

Hom.:

Cov.:

AF XY:

0.000502

AC XY:

365

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

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:

0.00620

Gnomad4 NFE exome

AF:

0.000358

Gnomad4 OTH exome

AF:

0.000613

GnomAD4 genome

AF:

0.000421

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00340

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000399

Hom.:

Bravo

AF:

0.000204

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00101

AC:

122

EpiCase

AF:

0.000164

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Bloom syndrome

Uncertain:2Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 22, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	May 26, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	May 31, 2023	The BLM c.2362C>A (p.Leu788Ile) missense change has a maximum subpopulation frequency of 0.081% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in one individual with breast cancer (PMID: 23028338), and in cases with Langerhans cell histiocytosis (PMID: 33332384), colorectal cancer (PMID: 28944238) and one suspected Lynch syndrome (PMID: 32660107). It has also identified in 2 of 1358 control individuals collected as part of non-cancer studies (PMID: 29641532). To our knowledge, this variant has not been reported in individuals with Bloom syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 09, 2020

- -

BLM-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2022

The BLM c.2362C>A variant is predicted to result in the amino acid substitution p.Leu788Ile. This variant was reported as variant of uncertain significance in an individual with suspected Lynch syndrome, who also carried a missense variant in WRN (Table S1, Olkinuora et al 2020. PubMed ID: 32660107). This variant is also reported in one individual with breast cancer (Table S4, Thompson et al. 2012. PubMed ID: 23028338). The p.Leu788Ile substitution is predicted with neutral effects for stability (Table 2, Sora and Otamendi et al. 2022 (preprint), https://www.biorxiv.org/content/10.1101/2022.09.02.506350v1.full.pdf). This variant is reported in 0.57% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-91312417-C-A). In ClinVar, this variant is interpreted as benign/likely benign/uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127485/?new_evidence=false). This variant could be benign, however, due to the small cohort sizes we interpret these data as inconclusive. At this time, the clinical significance of this variant is uncertain. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 07, 2020

Observed in individuals with a personal history of breast cancer (Thompson et al., 2012); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23028338) -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2020

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.14

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.13

T;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

D;D

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.014

T;T

MetaSVM

Uncertain

-0.049

MutationAssessor

Uncertain

2.2

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.8

N;N

REVEL

Uncertain

0.50

Sift

Uncertain

0.012

D;D

Sift4G

Uncertain

0.039

D;D

Polyphen

0.98

D;.

Vest4

0.49

MVP

0.88

MPC

0.49

ClinPred

0.12

GERP RS

4.4

Varity_R

0.81

gMVP

0.64

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