NM_000057.4:c.2603C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000057.4(BLM):c.2603C>T(p.Pro868Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0661 in 1,612,548 control chromosomes in the GnomAD database, including 3,984 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.065 ( 351 hom., cov: 32)

Exomes 𝑓: 0.066 ( 3633 hom. )

Consequence

BLM
NM_000057.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18O:1

Conservation

PhyloP100: 5.73

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 (MetaRNN=0.009349495).

BP6

Variant 15-90782869-C-T is Benign according to our data. Variant chr15-90782869-C-T is described in ClinVar as [Benign]. Clinvar id is 92393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-90782869-C-T is described in Lovd as [Benign]. Variant chr15-90782869-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0673 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLM	NM_000057.4 link	c.2603C>T	p.Pro868Leu	missense_variant	Exon 13 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.2603C>T	p.Pro868Leu	missense_variant	Exon 13 of 22	1	NM_000057.4	ENSP00000347232.3		P54132

Frequencies

GnomAD3 genomes

AF:

0.0655

AC:

9956

AN:

151896

Hom.:

352

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0664

Gnomad AMI

AF:

0.0615

Gnomad AMR

AF:

0.0554

Gnomad ASJ

AF:

0.0309

Gnomad EAS

AF:

0.000962

Gnomad SAS

AF:

0.0482

Gnomad FIN

AF:

0.110

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0689

Gnomad OTH

AF:

0.0556

GnomAD3 exomes

AF:

0.0556

AC:

13969

AN:

251184

Hom.:

493

AF XY:

0.0558

AC XY:

7575

AN XY:

135768

show subpopulations

Gnomad AFR exome

AF:

0.0675

Gnomad AMR exome

AF:

0.0371

Gnomad ASJ exome

AF:

0.0393

Gnomad EAS exome

AF:

0.000435

Gnomad SAS exome

AF:

0.0422

Gnomad FIN exome

AF:

0.102

Gnomad NFE exome

AF:

0.0649

Gnomad OTH exome

AF:

0.0534

GnomAD4 exome

AF:

0.0661

AC:

96587

AN:

1460534

Hom.:

3633

Cov.:

AF XY:

0.0654

AC XY:

47558

AN XY:

726652

show subpopulations

Gnomad4 AFR exome

AF:

0.0639

Gnomad4 AMR exome

AF:

0.0388

Gnomad4 ASJ exome

AF:

0.0371

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.0443

Gnomad4 FIN exome

AF:

0.101

Gnomad4 NFE exome

AF:

0.0708

Gnomad4 OTH exome

AF:

0.0616

GnomAD4 genome

AF:

0.0655

AC:

9956

AN:

152014

Hom.:

351

Cov.:

AF XY:

0.0656

AC XY:

4870

AN XY:

74280

show subpopulations

Gnomad4 AFR

AF:

0.0663

Gnomad4 AMR

AF:

0.0552

Gnomad4 ASJ

AF:

0.0309

Gnomad4 EAS

AF:

0.000965

Gnomad4 SAS

AF:

0.0478

Gnomad4 FIN

AF:

0.110

Gnomad4 NFE

AF:

0.0689

Gnomad4 OTH

AF:

0.0550

Alfa

AF:

0.0624

Hom.:

581

Bravo

AF:

0.0611

TwinsUK

AF:

0.0725

AC:

269

ALSPAC

AF:

0.0771

AC:

297

ESP6500AA

AF:

0.0735

AC:

323

ESP6500EA

AF:

0.0653

AC:

561

ExAC

AF:

0.0556

AC:

6747

Asia WGS

AF:

0.0210

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:18Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bloom syndrome

Benign:8

Mar 06, 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. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 24, 2014

Pathway Genomics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 20, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 18, 2021

Genome-Nilou Lab

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:4Other:1

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. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

not provided

Benign:4

Aug 31, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The BLM c.2603C>T (p.Pro868Leu) variant involves the alteration of a conserved nucleotide. 2/2 in silico tools predict a damaging outcome for this variant. This variant was found in 6732/120402 control chromosomes (223 homozygotes) at a frequency of 0.0559127, which is approximately 16 times the estimated maximal expected allele frequency of a pathogenic BLM variant (0.0035355), suggesting this variant is likely a benign polymorphism. Functional studies suggest partial loss of funciton (Mirzaei_2012, Shastri_2015), however the prevalence in the general population as well as numerous homozygous occurrences indicate this variant is insufficient for full-scale Bloom syndrome. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29484706, 24728327, 24816114, 26788541, 27153395, 19945966, 23129629) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hereditary disease

Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Aug 12, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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

0.18

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.90

D;D

MetaRNN

Benign

0.0093

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.4

M;.

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-6.3

D;D

REVEL

Benign

0.18

Sift

Uncertain

0.028

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

0.73

P;.

Vest4

0.25

MPC

0.46

ClinPred

0.061

GERP RS

5.5

Varity_R

0.39

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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