Genetic Variant BLM:c.4076+4T>G (chr15-90811410-T-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000057.4(BLM):c.4076+4T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00451 in 1,613,300 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0044 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0045 ( 33 hom. )

Consequence

BLM
NM_000057.4 splice_region, intron

Scores

Splicing: ADA: 0.00003625

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: -0.769

Publications

8 publications found

Variant links:

COSMIC-nc: COSV104665659

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:

ENSG00000287061 (HGNC:):

ENSG00000287061 links:

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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=-0.93).

BP6

Variant 15-90811410-T-G is Benign according to our data. Variant chr15-90811410-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00444 (677/152312) while in subpopulation AMR AF = 0.00732 (112/15302). AF 95% confidence interval is 0.00622. There are 5 homozygotes in GnomAd4. There are 342 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR,AD gene

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.4076+4T>G	splice_region intron	N/A	NP_000048.1	P54132
BLM	NM_001287246.2		c.4076+4T>G	splice_region intron	N/A	NP_001274175.1	P54132
BLM	NM_001287247.2		c.3683+4T>G	splice_region 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.4076+4T>G	splice_region intron	N/A	ENSP00000347232.3	P54132
BLM	ENST00000560509.5	TSL:1	c.3683+4T>G	splice_region intron	N/A	ENSP00000454158.1	H0YNU5
BLM	ENST00000559724.5	TSL:1	n.*3000+4T>G	splice_region intron	N/A	ENSP00000453359.1	H0YLV8

Frequencies

GnomAD3 genomes

AF:

0.00445

AC:

677

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00733

Gnomad ASJ

AF:

0.0360

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00754

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.00406

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.00443

AC:

1112

AN:

250928

AF XY:

0.00471

show subpopulations

Gnomad AFR exome

AF:

0.000555

Gnomad AMR exome

AF:

0.00327

Gnomad ASJ exome

AF:

0.0330

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00472

Gnomad NFE exome

AF:

0.00380

Gnomad OTH exome

AF:

0.00668

GnomAD4 exome

AF:

0.00452

AC:

6604

AN:

1460988

Hom.:

Cov.:

AF XY:

0.00463

AC XY:

3362

AN XY:

726850

show subpopulations

African (AFR)

AF:

0.00167

AC:

AN:

33452

American (AMR)

AF:

0.00356

AC:

159

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0331

AC:

864

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00266

AC:

229

AN:

86234

European-Finnish (FIN)

AF:

0.00375

AC:

200

AN:

53370

Middle Eastern (MID)

AF:

0.0257

AC:

148

AN:

5768

European-Non Finnish (NFE)

AF:

0.00405

AC:

4500

AN:

1111250

Other (OTH)

AF:

0.00742

AC:

448

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

335

670

1006

1341

1676

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

384

576

768

960

<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:

0.00444

AC:

677

AN:

152312

Hom.:

Cov.:

AF XY:

0.00459

AC XY:

342

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000794

AC:

AN:

41560

American (AMR)

AF:

0.00732

AC:

112

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0360

AC:

125

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00228

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00754

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00406

AC:

276

AN:

68032

Other (OTH)

AF:

0.00992

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

109

145

181

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00429

Hom.:

Bravo

AF:

0.00483

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.00600

EpiControl

AF:

0.00581

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Bloom syndrome (6)

not provided (5)

not specified (4)

Hereditary cancer-predisposing syndrome (3)

BLM-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

2.3

(source)

DANN

Benign

0.34

PhyloP100

-0.77

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000036

dbscSNV1_RF

Benign

0.018

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

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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