rs28385029

Positions:

• chr15-90765475-G-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
BLM	NM_000057.4	c.2193+61G>C		intron_variant		ENST00000355112.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLM	ENST00000355112.8	c.2193+61G>C		intron_variant		1	NM_000057.4	P2

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

Gnomad4 AFR exome AF: 0.0616

Gnomad4 AMR exome AF: 0.0461

Gnomad4 ASJ exome AF: 0.0464

Gnomad4 EAS exome AF: 0.000211

Gnomad4 SAS exome AF: 0.0444

Gnomad4 FIN exome AF: 0.0992

Gnomad4 NFE exome AF: 0.0749

Gnomad4 OTH exome AF: 0.0671

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

Gnomad4 AFR AF: 0.0617

Gnomad4 AMR AF: 0.0630

Gnomad4 ASJ AF: 0.0395

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.0483

Gnomad4 FIN AF: 0.107

Gnomad4 NFE AF: 0.0773

Gnomad4 OTH AF: 0.0673

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Bloom syndrome Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

May 15, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.6
DANN	Benign	0.57

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

LitVar

Other links and lift over

dbSNP: rs28385029; hg19: chr15-91308705;