rs7167216

Positions:

Variant summary

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

The NM_000057.4(BLM):c.3961G>A(p.Val1321Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0721 in 1,614,020 control chromosomes in the GnomAD database, including 4,643 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.079 ( 547 hom., cov: 32)

Exomes 𝑓: 0.071 ( 4096 hom. )

Consequence

BLM
NM_000057.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: -0.636

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=0.0016637444).

BP6

Variant 15-90811291-G-A is Benign according to our data. Variant chr15-90811291-G-A is described in ClinVar as [Benign]. Clinvar id is 128530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-90811291-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0947 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BLM	NM_000057.4 linkuse as main transcript	c.3961G>A	p.Val1321Ile	missense_variant	21/22	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.3961G>A	p.Val1321Ile	missense_variant	21/22	1	NM_000057.4	ENSP00000347232	P2

Frequencies

GnomAD3 genomes

AF:

0.0790

AC:

12019

AN:

152054

Hom.:

545

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0971

Gnomad AMI

AF:

0.0647

Gnomad AMR

AF:

0.0591

Gnomad ASJ

AF:

0.0302

Gnomad EAS

AF:

0.0304

Gnomad SAS

AF:

0.0695

Gnomad FIN

AF:

0.140

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0707

Gnomad OTH

AF:

0.0672

GnomAD3 exomes

AF:

0.0661

AC:

16622

AN:

251418

Hom.:

675

AF XY:

0.0667

AC XY:

9066

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.0946

Gnomad AMR exome

AF:

0.0414

Gnomad ASJ exome

AF:

0.0395

Gnomad EAS exome

AF:

0.0241

Gnomad SAS exome

AF:

0.0644

Gnomad FIN exome

AF:

0.133

Gnomad NFE exome

AF:

0.0669

Gnomad OTH exome

AF:

0.0593

GnomAD4 exome

AF:

0.0714

AC:

104319

AN:

1461848

Hom.:

4096

Cov.:

AF XY:

0.0710

AC XY:

51641

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.0930

Gnomad4 AMR exome

AF:

0.0432

Gnomad4 ASJ exome

AF:

0.0372

Gnomad4 EAS exome

AF:

0.0326

Gnomad4 SAS exome

AF:

0.0650

Gnomad4 FIN exome

AF:

0.132

Gnomad4 NFE exome

AF:

0.0721

Gnomad4 OTH exome

AF:

0.0675

GnomAD4 genome

AF:

0.0791

AC:

12032

AN:

152172

Hom.:

547

Cov.:

AF XY:

0.0807

AC XY:

6001

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.0972

Gnomad4 AMR

AF:

0.0591

Gnomad4 ASJ

AF:

0.0302

Gnomad4 EAS

AF:

0.0305

Gnomad4 SAS

AF:

0.0690

Gnomad4 FIN

AF:

0.140

Gnomad4 NFE

AF:

0.0707

Gnomad4 OTH

AF:

0.0665

Alfa

AF:

0.0663

Hom.:

598

Bravo

AF:

0.0730

TwinsUK

AF:

0.0725

AC:

269

ALSPAC

AF:

0.0768

AC:

296

ESP6500AA

AF:

0.0928

AC:

408

ESP6500EA

AF:

0.0664

AC:

571

ExAC

AF:

0.0663

AC:

8052

Asia WGS

AF:

0.0440

AC:

151

AN:

3478

EpiCase

AF:

0.0643

EpiControl

AF:

0.0596

ClinVar

Significance: Benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bloom syndrome

Benign:6

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 04, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:2Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 24728327) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2016

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

0.070

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.34

DANN

Benign

0.96

DEOGEN2

Benign

0.081

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.49

T;T

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.43

N;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.43

N;N

REVEL

Benign

0.089

Sift

Benign

0.26

T;T

Sift4G

Benign

0.38

T;T

Polyphen

0.010

B;.

Vest4

0.023

MPC

0.073

ClinPred

0.0067

GERP RS

-4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.018

gMVP

0.11

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