Genetic Variant NM_000057.4:c.3945C>T (chr15-90811275-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000057.4(BLM):c.3945C>T(p.Leu1315Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 1,613,904 control chromosomes in the GnomAD database, including 23,851 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1315L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.15 ( 1886 hom., cov: 32)

Exomes 𝑓: 0.17 ( 21965 hom. )

Consequence

BLM
NM_000057.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -2.48

Publications

36 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 15-90811275-C-T is Benign according to our data. Variant chr15-90811275-C-T is described in ClinVar as Benign. ClinVar VariationId is 92396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.48 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.185 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	HGVSp	Effect	Exon Rank	Protein	UniProt
BLM	NM_000057.4	MANE Select	c.3945C>T	p.Leu1315Leu	synonymous	Exon 21 of 22	NP_000048.1	P54132
BLM	NM_001287246.2		c.3945C>T	p.Leu1315Leu	synonymous	Exon 22 of 23	NP_001274175.1	P54132
BLM	NM_001287247.2		c.3552C>T	p.Leu1184Leu	synonymous	Exon 19 of 20	NP_001274176.1	H0YNU5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BLM	ENST00000355112.8	TSL:1 MANE Select	c.3945C>T	p.Leu1315Leu	synonymous	Exon 21 of 22	ENSP00000347232.3	P54132
BLM	ENST00000560509.5	TSL:1	c.3552C>T	p.Leu1184Leu	synonymous	Exon 19 of 20	ENSP00000454158.1	H0YNU5
BLM	ENST00000559724.5	TSL:1	n.*2869C>T		non_coding_transcript_exon	Exon 21 of 22	ENSP00000453359.1	H0YLV8

Frequencies

GnomAD3 genomes

AF:

0.154

AC:

23349

AN:

151950

Hom.:

1888

Cov.:

show subpopulations

Gnomad AFR

AF:

0.119

Gnomad AMI

AF:

0.0965

Gnomad AMR

AF:

0.109

Gnomad ASJ

AF:

0.171

Gnomad EAS

AF:

0.177

Gnomad SAS

AF:

0.0921

Gnomad FIN

AF:

0.150

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.188

Gnomad OTH

AF:

0.151

GnomAD2 exomes

AF:

0.152

AC:

38099

AN:

251430

AF XY:

0.151

show subpopulations

Gnomad AFR exome

AF:

0.123

Gnomad AMR exome

AF:

0.0846

Gnomad ASJ exome

AF:

0.166

Gnomad EAS exome

AF:

0.177

Gnomad FIN exome

AF:

0.150

Gnomad NFE exome

AF:

0.188

Gnomad OTH exome

AF:

0.155

GnomAD4 exome

AF:

0.170

AC:

248784

AN:

1461836

Hom.:

21965

Cov.:

AF XY:

0.168

AC XY:

122369

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.116

AC:

3894

AN:

33478

American (AMR)

AF:

0.0896

AC:

4006

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.165

AC:

4323

AN:

26136

East Asian (EAS)

AF:

0.174

AC:

6923

AN:

39700

South Asian (SAS)

AF:

0.0888

AC:

7656

AN:

86258

European-Finnish (FIN)

AF:

0.150

AC:

8016

AN:

53416

Middle Eastern (MID)

AF:

0.140

AC:

808

AN:

5760

European-Non Finnish (NFE)

AF:

0.183

AC:

203326

AN:

1111972

Other (OTH)

AF:

0.163

AC:

9832

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

12670

25339

38009

50678

63348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6910

13820

20730

27640

34550

<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:

0.154

AC:

23351

AN:

152068

Hom.:

1886

Cov.:

AF XY:

0.150

AC XY:

11173

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.119

AC:

4932

AN:

41474

American (AMR)

AF:

0.109

AC:

1659

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.171

AC:

595

AN:

3470

East Asian (EAS)

AF:

0.177

AC:

915

AN:

5160

South Asian (SAS)

AF:

0.0930

AC:

448

AN:

4816

European-Finnish (FIN)

AF:

0.150

AC:

1581

AN:

10562

Middle Eastern (MID)

AF:

0.163

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.188

AC:

12769

AN:

68014

Other (OTH)

AF:

0.150

AC:

316

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1031

2062

3093

4124

5155

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

252

504

756

1008

1260

<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:

0.170

Hom.:

3611

Bravo

AF:

0.149

Asia WGS

AF:

0.138

AC:

482

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Bloom syndrome (6)

not specified (4)

Hereditary cancer-predisposing syndrome (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.061

(source)

DANN

Benign

0.51

PhyloP100

-2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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