Genetic Variant BLM:c.2074+1023C>G (chr15-90764180-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000057.4(BLM):c.2074+1023C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.52 in 149,464 control chromosomes in the GnomAD database, including 20,467 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.52 ( 20467 hom., cov: 28)

Consequence

BLM
NM_000057.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0180

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

Bloom syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health, Genomics England PanelApp, ClinGen, Laboratory for Molecular Medicine
osteosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
colorectal cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
breast cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
hereditary nonpolyposis colon cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

BLM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.547 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000057.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
BLM	NM_000057.4	MANE Select	c.2074+1023C>G	intron	N/A	NP_000048.1	P54132
BLM	NM_001287246.2		c.2074+1023C>G	intron	N/A	NP_001274175.1	P54132
BLM	NM_001287247.2		c.2074+1023C>G	intron	N/A	NP_001274176.1	H0YNU5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
BLM	ENST00000355112.8	TSL:1 MANE Select	c.2074+1023C>G	intron	N/A	ENSP00000347232.3	P54132
BLM	ENST00000560509.5	TSL:1	c.2074+1023C>G	intron	N/A	ENSP00000454158.1	H0YNU5
BLM	ENST00000559724.5	TSL:1	n.*998+1023C>G	intron	N/A	ENSP00000453359.1	H0YLV8

Frequencies

GnomAD3 genomes

AF:

0.520

AC:

77648

AN:

149414

Hom.:

20461

Cov.:

show subpopulations

Gnomad AFR

AF:

0.523

Gnomad AMI

AF:

0.386

Gnomad AMR

AF:

0.426

Gnomad ASJ

AF:

0.471

Gnomad EAS

AF:

0.379

Gnomad SAS

AF:

0.488

Gnomad FIN

AF:

0.554

Gnomad MID

AF:

0.416

Gnomad NFE

AF:

0.552

Gnomad OTH

AF:

0.501

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.520

AC:

77671

AN:

149464

Hom.:

20467

Cov.:

AF XY:

0.515

AC XY:

37474

AN XY:

72776

show subpopulations

African (AFR)

AF:

0.523

AC:

21306

AN:

40710

American (AMR)

AF:

0.426

AC:

6381

AN:

14982

Ashkenazi Jewish (ASJ)

AF:

0.471

AC:

1631

AN:

3464

East Asian (EAS)

AF:

0.380

AC:

1953

AN:

5134

South Asian (SAS)

AF:

0.487

AC:

2316

AN:

4758

European-Finnish (FIN)

AF:

0.554

AC:

5312

AN:

9582

Middle Eastern (MID)

AF:

0.413

AC:

118

AN:

286

European-Non Finnish (NFE)

AF:

0.551

AC:

37261

AN:

67564

Other (OTH)

AF:

0.502

AC:

1044

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1795

3590

5384

7179

8974

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

694

1388

2082

2776

3470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.432

Hom.:

1277

Bravo

AF:

0.506

Asia WGS

AF:

0.453

AC:

1578

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

6.3

(source)

DANN

Benign

0.72

PhyloP100

-0.018

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over