Genetic Variant BLM:p.Val1205Ile (chr15-90804221-G-A) – 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.3613G>A(p.Val1205Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000388 in 1,614,150 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1205A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0023 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

BLM
NM_000057.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: 4.03

Publications

7 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:

ENSG00000300894 (HGNC:):

ENSG00000300894 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 (MetaRNN=0.005327344).

BP6

Variant 15-90804221-G-A is Benign according to our data. Variant chr15-90804221-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 133701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00227 (346/152316) while in subpopulation AFR AF = 0.00756 (314/41558). AF 95% confidence interval is 0.00687. There are 2 homozygotes in GnomAd4. There are 154 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 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	HGVSp	Effect	Exon Rank	Protein	UniProt
BLM	NM_000057.4	MANE Select	c.3613G>A	p.Val1205Ile	missense	Exon 19 of 22	NP_000048.1	P54132
BLM	NM_001287246.2		c.3613G>A	p.Val1205Ile	missense	Exon 20 of 23	NP_001274175.1	P54132
BLM	NM_001287248.2		c.2488G>A	p.Val830Ile	missense	Exon 19 of 22	NP_001274177.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BLM	ENST00000355112.8	TSL:1 MANE Select	c.3613G>A	p.Val1205Ile	missense	Exon 19 of 22	ENSP00000347232.3	P54132
BLM	ENST00000560509.5	TSL:1	c.3359-4916G>A		intron	N/A	ENSP00000454158.1	H0YNU5
BLM	ENST00000559724.5	TSL:1	n.*2537G>A		non_coding_transcript_exon	Exon 19 of 22	ENSP00000453359.1	H0YLV8

Frequencies

GnomAD3 genomes

AF:

0.00227

AC:

345

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00755

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.000593

AC:

149

AN:

251308

AF XY:

0.000493

show subpopulations

Gnomad AFR exome

AF:

0.00807

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000192

AC:

280

AN:

1461834

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

117

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.00642

AC:

215

AN:

33480

American (AMR)

AF:

0.000626

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111966

Other (OTH)

AF:

0.000480

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.00227

AC:

346

AN:

152316

Hom.:

Cov.:

AF XY:

0.00207

AC XY:

154

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00756

AC:

314

AN:

41558

American (AMR)

AF:

0.00157

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68036

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000858

Hom.:

Bravo

AF:

0.00243

ESP6500AA

AF:

0.00660

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000651

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Bloom syndrome (5)

Hereditary cancer-predisposing syndrome (2)

not specified (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

Eigen

Benign

0.041

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.0094

MetaRNN

Benign

0.0053

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

4.0

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.92

REVEL

Benign

0.048

Sift

Benign

0.056

Sift4G

Benign

0.12

Polyphen

0.14

Vest4

0.14

MVP

0.74

MPC

0.085

ClinPred

0.018

GERP RS

5.8

Varity_R

0.12

gMVP

0.30

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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