dbSNP rs28385009: BLM:p.His374His (chr15-90760181-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000057.4(BLM):c.1122T>C(p.His374His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00383 in 1,612,700 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0046 ( 11 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 83 hom. )

Consequence

BLM
NM_000057.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.84

Publications

10 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=-0.93).

BP6

Variant 15-90760181-T-C is Benign according to our data. Variant chr15-90760181-T-C is described in ClinVar as Benign. ClinVar VariationId is 136510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.84 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00462 (704/152288) while in subpopulation EAS AF = 0.0247 (128/5184). AF 95% confidence interval is 0.0212. There are 11 homozygotes in GnomAd4. There are 480 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 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.1122T>C	p.His374His	synonymous	Exon 6 of 22	NP_000048.1	P54132
BLM	NM_001287246.2		c.1122T>C	p.His374His	synonymous	Exon 7 of 23	NP_001274175.1	P54132
BLM	NM_001287247.2		c.1122T>C	p.His374His	synonymous	Exon 6 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.1122T>C	p.His374His	synonymous	Exon 6 of 22	ENSP00000347232.3	P54132
BLM	ENST00000560509.5	TSL:1	c.1122T>C	p.His374His	synonymous	Exon 6 of 20	ENSP00000454158.1	H0YNU5
BLM	ENST00000559724.5	TSL:1	n.*46T>C		non_coding_transcript_exon	Exon 6 of 22	ENSP00000453359.1	H0YLV8

Frequencies

GnomAD3 genomes

AF:

0.00463

AC:

704

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0246

Gnomad SAS

AF:

0.0215

Gnomad FIN

AF:

0.0324

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00134

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00802

AC:

2017

AN:

251408

AF XY:

0.00864

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00298

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0229

Gnomad FIN exome

AF:

0.0313

Gnomad NFE exome

AF:

0.00128

Gnomad OTH exome

AF:

0.00473

GnomAD4 exome

AF:

0.00374

AC:

5467

AN:

1460412

Hom.:

Cov.:

AF XY:

0.00420

AC XY:

3050

AN XY:

726656

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33448

American (AMR)

AF:

0.00282

AC:

126

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.0314

AC:

1244

AN:

39676

South Asian (SAS)

AF:

0.0192

AC:

1655

AN:

86228

European-Finnish (FIN)

AF:

0.0309

AC:

1653

AN:

53414

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000491

AC:

545

AN:

1110690

Other (OTH)

AF:

0.00381

AC:

230

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

312

624

935

1247

1559

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.00462

AC:

704

AN:

152288

Hom.:

Cov.:

AF XY:

0.00645

AC XY:

480

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41558

American (AMR)

AF:

0.000915

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0247

AC:

128

AN:

5184

South Asian (SAS)

AF:

0.0213

AC:

103

AN:

4828

European-Finnish (FIN)

AF:

0.0324

AC:

343

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00134

AC:

AN:

68030

Other (OTH)

AF:

0.00615

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

129

161

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:

0.00142

Hom.:

Bravo

AF:

0.00191

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000533

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Bloom syndrome (5)

not specified (3)

Hereditary cancer-predisposing syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.12

(source)

DANN

Benign

0.53

PhyloP100

-2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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