15-90766984-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_000057.4(BLM):​c.2268A>G​(p.Lys756Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,599,836 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.0017 ( 1 hom., cov: 32)
Exomes š‘“: 0.0024 ( 4 hom. )

Consequence

BLM
NM_000057.4 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:13

Conservation

PhyloP100: 1.03
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.56).
BP6
Variant 15-90766984-A-G is Benign according to our data. Variant chr15-90766984-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 136514.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=4, Uncertain_significance=1}. Variant chr15-90766984-A-G is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=1.03 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00165 (252/152348) while in subpopulation NFE AF= 0.00294 (200/68022). AF 95% confidence interval is 0.00261. There are 1 homozygotes in gnomad4. There are 105 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BLMNM_000057.4 linkc.2268A>G p.Lys756Lys synonymous_variant Exon 10 of 22 ENST00000355112.8 NP_000048.1 P54132

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BLMENST00000355112.8 linkc.2268A>G p.Lys756Lys synonymous_variant Exon 10 of 22 1 NM_000057.4 ENSP00000347232.3 P54132

Frequencies

GnomAD3 genomes
AF:
0.00166
AC:
252
AN:
152230
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000314
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000654
Gnomad ASJ
AF:
0.00288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00227
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00294
Gnomad OTH
AF:
0.00334
GnomAD3 exomes
AF:
0.00187
AC:
466
AN:
249810
Hom.:
0
AF XY:
0.00205
AC XY:
277
AN XY:
135102
show subpopulations
Gnomad AFR exome
AF:
0.000250
Gnomad AMR exome
AF:
0.000902
Gnomad ASJ exome
AF:
0.00458
Gnomad EAS exome
AF:
0.0000546
Gnomad SAS exome
AF:
0.00263
Gnomad FIN exome
AF:
0.0000924
Gnomad NFE exome
AF:
0.00259
Gnomad OTH exome
AF:
0.00164
GnomAD4 exome
AF:
0.00237
AC:
3435
AN:
1447488
Hom.:
4
Cov.:
29
AF XY:
0.00242
AC XY:
1747
AN XY:
720666
show subpopulations
Gnomad4 AFR exome
AF:
0.000422
Gnomad4 AMR exome
AF:
0.000875
Gnomad4 ASJ exome
AF:
0.00411
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00294
Gnomad4 FIN exome
AF:
0.0000938
Gnomad4 NFE exome
AF:
0.00259
Gnomad4 OTH exome
AF:
0.00237
GnomAD4 genome
AF:
0.00165
AC:
252
AN:
152348
Hom.:
1
Cov.:
32
AF XY:
0.00141
AC XY:
105
AN XY:
74508
show subpopulations
Gnomad4 AFR
AF:
0.000313
Gnomad4 AMR
AF:
0.000653
Gnomad4 ASJ
AF:
0.00288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00228
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00294
Gnomad4 OTH
AF:
0.00331
Alfa
AF:
0.00205
Hom.:
0
Bravo
AF:
0.00157
Asia WGS
AF:
0.00115
AC:
4
AN:
3476

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:13
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Bloom syndrome Uncertain:1Benign:3
May 15, 2017
Natera, Inc.
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 18, 2021
Genome-Nilou Lab
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:4
Nov 22, 2021
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 25, 2013
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jun 24, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: BLM c.2268A>G alters a non-conserved nucleotide resulting in a synonymous change. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0023 in 1599836 control chromosomes, predominantly at a frequency of 0.004 within the South Asian subpopulation in the gnomAD database (gnomAD v4.1.0). The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.13 fold of the estimated maximal expected allele frequency for a pathogenic variant in BLM causing Bloom Syndrome phenotype (0.0035). c.2268A>G has been reported in the literature in at least an individual from families with an accumulation of colorectal cancers or with only one sporadic case of very early onset colorectal cancer (example: Djursby_2020). These report(s) 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. The following publication have been ascertained in the context of this evaluation (PMID: 33193653). ClinVar contains an entry for this variant (Variation ID: 136514). Based on the evidence outlined above, the variant was classified as benign. -

Feb 24, 2016
Eurofins Ntd Llc (ga)
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:4
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BLM: BP4, BP7 -

Oct 07, 2022
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2
Sep 30, 2016
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jul 13, 2021
Sema4, Sema4
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.56
CADD
Benign
7.7
DANN
Benign
0.53

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.

Other links and lift over

dbSNP: rs146013879; hg19: chr15-91310214; COSMIC: COSV61926845; API