15-90747403-T-C

Position:

chr15-90747403-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000057.4(BLM):c.11T>C(p.Val4Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00155 in 1,609,200 control chromosomes in the GnomAD database, including 3 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. V4D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0016 ( 3 hom. )

Consequence

BLM
NM_000057.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:6

Conservation

PhyloP100: 4.14

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017179012).

BP6

Variant 15-90747403-T-C is Benign according to our data. Variant chr15-90747403-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127473.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=11, Likely_benign=5, Benign=1}. Variant chr15-90747403-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00102 (156/152298) while in subpopulation NFE AF= 0.00203 (138/68016). AF 95% confidence interval is 0.00175. There are 0 homozygotes in gnomad4. There are 63 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLM	NM_000057.4 linkuse as main transcript	c.11T>C	p.Val4Ala	missense_variant	2/22	ENST00000355112.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLM	ENST00000355112.8 linkuse as main transcript	c.11T>C	p.Val4Ala	missense_variant	2/22	1	NM_000057.4	P2

Frequencies

GnomAD3 genomes

AF:

0.00103

AC:

156

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00203

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00113

AC:

278

AN:

245310

Hom.:

AF XY:

0.00118

AC XY:

156

AN XY:

132512

show subpopulations

Gnomad AFR exome

AF:

0.000321

Gnomad AMR exome

AF:

0.000526

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000334

Gnomad FIN exome

AF:

0.000375

Gnomad NFE exome

AF:

0.00216

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.00161

AC:

2339

AN:

1456902

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

1189

AN XY:

724400

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000472

Gnomad4 ASJ exome

AF:

0.0000771

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000701

Gnomad4 FIN exome

AF:

0.000416

Gnomad4 NFE exome

AF:

0.00200

Gnomad4 OTH exome

AF:

0.000931

GnomAD4 genome

AF:

0.00102

AC:

156

AN:

152298

Hom.:

Cov.:

AF XY:

0.000846

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00203

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00219

Hom.:

Bravo

AF:

0.000997

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000910

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00128

AC:

156

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Bloom syndrome

Uncertain:5Benign:2

Uncertain significance, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Jan 01, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	May 27, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 02, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 23, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	May 13, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Uncertain:3Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31159747, 23028338, 19917125, 30666157) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2020	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 27, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Oct 07, 2021	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 18, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 03, 2022	Variant summary: BLM c.11T>C (p.Val4Ala) results in a non-conservative amino acid change located in the Bloom syndrome protein, N-terminal domain 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 0.0011 in 245310 control chromosomes. This frequency is not significantly higher than the estimated maximum frequency expected for a pathogenic variant in BLM causing Bloom Syndrome (0.0011 vs 0.0035), allowing no conclusion about variant significance. c.11T>C has been reported in the literature in individuals affected with Prostate cancer and Non-Hodkin Lymphoma (NHL), and in Hereditary Breast and Ovarian Cancer (HBOC) families (e.g. Hunter_2016, Schuetz_2009, Thompson_2012, Bonache_2018, Tsaousis_2019). These reports do not provide unequivocal conclusions about association of the variant with Bloom Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (uncertain significance, n=12; benign/likely benign, n=3). Based on the evidence outlined above, the variant was classified as uncertain significance. -

BLM-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 13, 2022

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

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.046

MetaRNN

Benign

0.017

T;T

MetaSVM

Benign

-0.64

MutationAssessor

Uncertain

2.3

M;.

MutationTaster

Benign

0.52

N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.12

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.030

D;D

Polyphen

0.61

P;.

Vest4

0.30

MVP

0.85

MPC

0.22

ClinPred

0.017

GERP RS

5.9

Varity_R

0.16

gMVP

0.062

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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