Genetic Variant BLM:c.2193+61G>C (chr15-90765475-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000057.4(BLM):c.2193+61G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0688 in 1,292,324 control chromosomes in the GnomAD database, including 3,459 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.069 ( 424 hom., cov: 32)

Exomes 𝑓: 0.069 ( 3035 hom. )

Consequence

BLM
NM_000057.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.20

Publications

3 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 15-90765475-G-C is Benign according to our data. Variant chr15-90765475-G-C is described in ClinVar as Benign. ClinVar VariationId is 1258106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0756 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.2193+61G>C	intron	N/A	NP_000048.1	P54132
BLM	NM_001287246.2		c.2193+61G>C	intron	N/A	NP_001274175.1	P54132
BLM	NM_001287247.2		c.2193+61G>C	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.2193+61G>C	intron	N/A	ENSP00000347232.3	P54132
BLM	ENST00000560509.5	TSL:1	c.2193+61G>C	intron	N/A	ENSP00000454158.1	H0YNU5
BLM	ENST00000559724.5	TSL:1	n.*1117+61G>C	intron	N/A	ENSP00000453359.1	H0YLV8

Frequencies

GnomAD3 genomes

AF:

0.0690

AC:

10498

AN:

152090

Hom.:

422

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0615

Gnomad AMI

AF:

0.0636

Gnomad AMR

AF:

0.0632

Gnomad ASJ

AF:

0.0395

Gnomad EAS

AF:

0.000962

Gnomad SAS

AF:

0.0485

Gnomad FIN

AF:

0.107

Gnomad MID

AF:

0.0318

Gnomad NFE

AF:

0.0773

Gnomad OTH

AF:

0.0680

GnomAD4 exome

AF:

0.0688

AC:

78409

AN:

1140116

Hom.:

3035

AF XY:

0.0683

AC XY:

39741

AN XY:

581494

show subpopulations

African (AFR)

AF:

0.0616

AC:

1651

AN:

26810

American (AMR)

AF:

0.0461

AC:

2004

AN:

43494

Ashkenazi Jewish (ASJ)

AF:

0.0464

AC:

1118

AN:

24110

East Asian (EAS)

AF:

0.000211

AC:

AN:

37914

South Asian (SAS)

AF:

0.0444

AC:

3506

AN:

79046

European-Finnish (FIN)

AF:

0.0992

AC:

4556

AN:

45924

Middle Eastern (MID)

AF:

0.0341

AC:

174

AN:

5110

European-Non Finnish (NFE)

AF:

0.0749

AC:

62044

AN:

827844

Other (OTH)

AF:

0.0671

AC:

3348

AN:

49864

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

3714

7428

11143

14857

18571

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1978

3956

5934

7912

9890

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0691

AC:

10511

AN:

152208

Hom.:

424

Cov.:

AF XY:

0.0687

AC XY:

5111

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.0617

AC:

2564

AN:

41534

American (AMR)

AF:

0.0630

AC:

964

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0395

AC:

137

AN:

3470

East Asian (EAS)

AF:

0.000965

AC:

AN:

5184

South Asian (SAS)

AF:

0.0483

AC:

233

AN:

4820

European-Finnish (FIN)

AF:

0.107

AC:

1138

AN:

10586

Middle Eastern (MID)

AF:

0.0342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0773

AC:

5260

AN:

68008

Other (OTH)

AF:

0.0673

AC:

142

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

512

1024

1536

2048

2560

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

240

360

480

600

<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:

0.0709

Hom.:

Bravo

AF:

0.0656

Asia WGS

AF:

0.0250

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Bloom syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

8.6

(source)

DANN

Benign

0.57

PhyloP100

1.2

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over