rs184657475

Positions:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_000057.4(BLM):c.1044G>A(p.Met348Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000824 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M348T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000083 ( 0 hom. )

Consequence

BLM
NM_000057.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 0.169

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 -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0044721067).

BP6

Variant 15-90754895-G-A is Benign according to our data. Variant chr15-90754895-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 413284.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=1}. Variant chr15-90754895-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000828 (121/1461678) while in subpopulation EAS AF= 0.0028 (111/39674). AF 95% confidence interval is 0.00238. There are 0 homozygotes in gnomad4_exome. There are 49 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLM	NM_000057.4 linkuse as main transcript	c.1044G>A	p.Met348Ile	missense_variant	5/22	ENST00000355112.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLM	ENST00000355112.8 linkuse as main transcript	c.1044G>A	p.Met348Ile	missense_variant	5/22	1	NM_000057.4	P2

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152122

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:

0.00231

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000243

AC:

AN:

250878

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135604

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00327

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000828

AC:

121

AN:

1461678

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00280

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00231

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000140

ExAC

AF:

0.000231

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 28, 2017	Variant summary: The BLM c.1044G>A (p.Met348Ile) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 28/120196 control chromosomes at a frequency of 0.000233, which does not exceed the estimated maximal expected allele frequency of a pathogenic BLM variant (0.0035355). In addition, one clinical diagnostic laboratory classified this variant as likely benign. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 29, 2023	- -

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

May 06, 2022

DNA sequence analysis of the BLM gene demonstrated a sequence change, c.1044G>A, in exon 5 that results in an amino acid change, p.Met348Ile. This sequence change has been described in the gnomAD database with a frequency of 0.33% in the East Asian subpopulation (dbSNP rs184657475). The p.Met348Ile change affects a poorly conserved amino acid residue located in a domain of the BLM protein that is not known to be functional. The p.Met348Ile substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in individuals with BLM-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Met348Ile change remains unknown at this time. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Cancer Genomics Group, Japanese Foundation For Cancer Research

May 01, 2019

- -

BLM-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 01, 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). -

Bloom syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.65

CADD

Benign

5.2

DANN

Benign

0.68

DEOGEN2

Benign

0.084

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.48

T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.0045

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.78

N;N

REVEL

Benign

0.022

Sift

Uncertain

0.025

D;T

Sift4G

Benign

0.44

T;T

Polyphen

0.15

B;.

Vest4

0.19

MutPred

0.17

Gain of methylation at K347 (P = 0.0223);Gain of methylation at K347 (P = 0.0223);

MVP

0.60

MPC

0.098

ClinPred

0.014

GERP RS

-0.88

Varity_R

0.067

gMVP

0.071

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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