rs28385029

Variant names:

• chr15-90765475-G-C
• rs28385029
• NM_000057.4:c.2193+61G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000057.4(BLM):​c.2193+61G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0688 in 1,292,324 control chromosomes in the GnomAD database, including 3,459 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (424 hom., cov: 32)
  • Exomes 𝑓: 0.069 (3035 hom.)
• Consequence: BLM NM_000057.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.20
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 15-90765475-G-C is Benign according to our data. Variant chr15-90765475-G-C is described in ClinVar as Benign. ClinVar VariationId is 1258106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0756 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLM	NM_000057.4	c.2193+61G>C		intron_variant	Intron 9 of 21	ENST00000355112.8	NP_000048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLM	ENST00000355112.8	c.2193+61G>C		intron_variant	Intron 9 of 21	1	NM_000057.4	ENSP00000347232.3

Frequencies

GnomAD3 genomes AF: 0.0690 AC: 10498 AN: 152090 Hom.: 422 Cov.: 32

Gnomad AFR AF: 0.0615

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.0632

Gnomad ASJ AF: 0.0395

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0485

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.0773

Gnomad OTH AF: 0.0680

GnomAD4 exome AF: 0.0688 AC: 78409 AN: 1140116 Hom.: 3035 AF XY: 0.0683 AC XY: 39741 AN XY: 581494

African (AFR) AF: 0.0616 AC: 1651 AN: 26810

American (AMR) AF: 0.0461 AC: 2004 AN: 43494

Ashkenazi Jewish (ASJ) AF: 0.0464 AC: 1118 AN: 24110

East Asian (EAS) AF: 0.000211 AC: 8 AN: 37914

South Asian (SAS) AF: 0.0444 AC: 3506 AN: 79046

European-Finnish (FIN) AF: 0.0992 AC: 4556 AN: 45924

Middle Eastern (MID) AF: 0.0341 AC: 174 AN: 5110

European-Non Finnish (NFE) AF: 0.0749 AC: 62044 AN: 827844

Other (OTH) AF: 0.0671 AC: 3348 AN: 49864

GnomAD4 genome AF: 0.0691 AC: 10511 AN: 152208 Hom.: 424 Cov.: 32 AF XY: 0.0687 AC XY: 5111 AN XY: 74416

African (AFR) AF: 0.0617 AC: 2564 AN: 41534

American (AMR) AF: 0.0630 AC: 964 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0395 AC: 137 AN: 3470

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5184

South Asian (SAS) AF: 0.0483 AC: 233 AN: 4820

European-Finnish (FIN) AF: 0.107 AC: 1138 AN: 10586

Middle Eastern (MID) AF: 0.0342 AC: 10 AN: 292

European-Non Finnish (NFE) AF: 0.0773 AC: 5260 AN: 68008

Other (OTH) AF: 0.0673 AC: 142 AN: 2110

Alfa AF: 0.0709 Hom.: 49

Bravo AF: 0.0656

Asia WGS AF: 0.0250 AC: 88 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bloom syndrome Benign:1

May 15, 2017

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.6
DANN	Benign	0.57
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs28385029; hg19: chr15-91308705;