Genetic Variant BLM:p.Arg643His (chr15-90763011-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000057.4(BLM):c.1928G>A(p.Arg643His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0047 in 1,613,418 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R643L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0049 ( 20 hom. )

Consequence

BLM
NM_000057.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:18O:1

Conservation

PhyloP100: 0.456

Publications

11 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: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Orphanet, Genomics England PanelApp, ClinGen
osteosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004977405).

BP6

Variant 15-90763011-G-A is Benign according to our data. Variant chr15-90763011-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127480.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00278 (424/152272) while in subpopulation NFE AF = 0.0045 (306/68010). AF 95% confidence interval is 0.00408. There are 1 homozygotes in GnomAd4. There are 189 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 20 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
BLM	NM_000057.4	MANE Select	c.1928G>A	p.Arg643His	missense	Exon 8 of 22	NP_000048.1
BLM	NM_001287246.2		c.1928G>A	p.Arg643His	missense	Exon 9 of 23	NP_001274175.1
BLM	NM_001287247.2		c.1928G>A	p.Arg643His	missense	Exon 8 of 20	NP_001274176.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BLM	ENST00000355112.8	TSL:1 MANE Select	c.1928G>A	p.Arg643His	missense	Exon 8 of 22	ENSP00000347232.3
BLM	ENST00000560509.5	TSL:1	c.1928G>A	p.Arg643His	missense	Exon 8 of 20	ENSP00000454158.1
BLM	ENST00000559724.5	TSL:1	n.*852G>A		non_coding_transcript_exon	Exon 8 of 22	ENSP00000453359.1

Frequencies

GnomAD3 genomes

AF:

0.00279

AC:

424

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000917

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00302

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00450

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00333

AC:

833

AN:

250174

AF XY:

0.00349

show subpopulations

Gnomad AFR exome

AF:

0.000867

Gnomad AMR exome

AF:

0.00134

Gnomad ASJ exome

AF:

0.00279

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00315

Gnomad NFE exome

AF:

0.00471

Gnomad OTH exome

AF:

0.00428

GnomAD4 exome

AF:

0.00490

AC:

7165

AN:

1461146

Hom.:

Cov.:

AF XY:

0.00476

AC XY:

3459

AN XY:

726812

show subpopulations

African (AFR)

AF:

0.000539

AC:

AN:

33404

American (AMR)

AF:

0.00137

AC:

AN:

44542

Ashkenazi Jewish (ASJ)

AF:

0.00349

AC:

AN:

26110

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39688

South Asian (SAS)

AF:

0.00394

AC:

339

AN:

86046

European-Finnish (FIN)

AF:

0.00240

AC:

128

AN:

53398

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00563

AC:

6262

AN:

1111832

Other (OTH)

AF:

0.00403

AC:

243

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

342

684

1027

1369

1711

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

246

492

738

984

1230

<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:

0.00278

AC:

424

AN:

152272

Hom.:

Cov.:

AF XY:

0.00254

AC XY:

189

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.000914

AC:

AN:

41560

American (AMR)

AF:

0.000719

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00331

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00302

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00450

AC:

306

AN:

68010

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

106

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:

0.00365

Hom.:

Bravo

AF:

0.00257

TwinsUK

AF:

0.0105

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00465

AC:

ExAC

AF:

0.00315

AC:

383

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00436

EpiControl

AF:

0.00391

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Bloom syndrome (6)

not provided (5)

not specified (6)

Hereditary cancer-predisposing syndrome (2)

BLM-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.51

CADD

Benign

2.8

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.078

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.77

M_CAP

Benign

0.034

MetaRNN

Benign

0.0050

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.015

PhyloP100

0.46

PrimateAI

Benign

0.20

PROVEAN

Benign

-1.0

REVEL

Benign

0.14

Sift

Benign

0.31

Sift4G

Benign

0.28

Polyphen

0.0040

Vest4

0.11

MVP

0.67

MPC

0.11

ClinPred

0.0095

GERP RS

-3.9

Varity_R

0.057

gMVP

0.50

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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