NM_000057.4:c.2193+84C>T

Variant names:

• chr15-90765498-C-T
• rs17181698
• NM_000057.4:c.2193+84C>T

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+84C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0699 in 1,121,778 control chromosomes in the GnomAD database, including 3,080 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (423 hom., cov: 32)
  • Exomes 𝑓: 0.070 (2657 hom.)
• Consequence: BLM NM_000057.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0840
• 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=-0.82).
• BP6: Variant 15-90765498-C-T is Benign according to our data. Variant chr15-90765498-C-T is described in ClinVar as Benign. ClinVar VariationId is 1235895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0753 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLM	NM_000057.4	c.2193+84C>T		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+84C>T		intron_variant	Intron 9 of 21	1	NM_000057.4	ENSP00000347232.3

Frequencies

GnomAD3 genomes AF: 0.0689 AC: 10478 AN: 152070 Hom.: 420 Cov.: 32

Gnomad AFR AF: 0.0615

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.0633

Gnomad ASJ AF: 0.0395

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0485

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0770

Gnomad OTH AF: 0.0677

GnomAD4 exome AF: 0.0701 AC: 67945 AN: 969590 Hom.: 2657 AF XY: 0.0693 AC XY: 34665 AN XY: 500246

African (AFR) AF: 0.0616 AC: 1418 AN: 23012

American (AMR) AF: 0.0477 AC: 1851 AN: 38772

Ashkenazi Jewish (ASJ) AF: 0.0471 AC: 1061 AN: 22518

East Asian (EAS) AF: 0.000557 AC: 20 AN: 35914

South Asian (SAS) AF: 0.0445 AC: 3230 AN: 72652

European-Finnish (FIN) AF: 0.100 AC: 4005 AN: 40048

Middle Eastern (MID) AF: 0.0358 AC: 162 AN: 4530

European-Non Finnish (NFE) AF: 0.0773 AC: 53224 AN: 688318

Other (OTH) AF: 0.0679 AC: 2974 AN: 43826

GnomAD4 genome AF: 0.0690 AC: 10494 AN: 152188 Hom.: 423 Cov.: 32 AF XY: 0.0687 AC XY: 5107 AN XY: 74390

African (AFR) AF: 0.0618 AC: 2566 AN: 41528

American (AMR) AF: 0.0632 AC: 966 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0395 AC: 137 AN: 3472

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5182

South Asian (SAS) AF: 0.0483 AC: 233 AN: 4824

European-Finnish (FIN) AF: 0.108 AC: 1140 AN: 10570

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0770 AC: 5236 AN: 68004

Other (OTH) AF: 0.0670 AC: 141 AN: 2106

Alfa AF: 0.0708 Hom.: 49

Bravo AF: 0.0655

Asia WGS AF: 0.0250 AC: 87 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.0
DANN	Benign	0.69
PhyloP100		-0.084
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: rs17181698; hg19: chr15-91308728;