NM_000057.4:c.3359-121_3359-120insA

Variant names:

• chr15-90803400-C-CA
• rs11377009
• NM_000057.4:c.3359-121_3359-120insA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000057.4(BLM):​c.3359-121_3359-120insA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.672 in 794,838 control chromosomes in the GnomAD database, including 181,083 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34669 hom., cov: 0)
  • Exomes 𝑓: 0.67 (146414 hom.)
• Consequence: BLM NM_000057.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.310
• Publications: 1 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

ENSG00000300894 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 15-90803400-C-CA is Benign according to our data. Variant chr15-90803400-C-CA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.822 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLM	NM_000057.4	c.3359-121_3359-120insA		intron_variant	Intron 17 of 21	ENST00000355112.8	NP_000048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLM	ENST00000355112.8	c.3359-121_3359-120insA		intron_variant	Intron 17 of 21	1	NM_000057.4	ENSP00000347232.3

Frequencies

GnomAD3 genomes AF: 0.672 AC: 102035 AN: 151760 Hom.: 34638 Cov.: 0

Gnomad AFR AF: 0.652

Gnomad AMI AF: 0.743

Gnomad AMR AF: 0.746

Gnomad ASJ AF: 0.700

Gnomad EAS AF: 0.843

Gnomad SAS AF: 0.667

Gnomad FIN AF: 0.632

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.660

Gnomad OTH AF: 0.670

GnomAD4 exome AF: 0.672 AC: 431760 AN: 642960 Hom.: 146414 AF XY: 0.670 AC XY: 224285 AN XY: 334894

African (AFR) AF: 0.663 AC: 11049 AN: 16654

American (AMR) AF: 0.783 AC: 22149 AN: 28276

Ashkenazi Jewish (ASJ) AF: 0.697 AC: 13076 AN: 18760

East Asian (EAS) AF: 0.832 AC: 26847 AN: 32286

South Asian (SAS) AF: 0.668 AC: 38256 AN: 57312

European-Finnish (FIN) AF: 0.633 AC: 29756 AN: 47016

Middle Eastern (MID) AF: 0.658 AC: 1750 AN: 2660

European-Non Finnish (NFE) AF: 0.655 AC: 267036 AN: 407598

Other (OTH) AF: 0.674 AC: 21841 AN: 32398

GnomAD4 genome AF: 0.672 AC: 102118 AN: 151878 Hom.: 34669 Cov.: 0 AF XY: 0.673 AC XY: 49942 AN XY: 74200

African (AFR) AF: 0.652 AC: 26994 AN: 41414

American (AMR) AF: 0.746 AC: 11384 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.700 AC: 2426 AN: 3466

East Asian (EAS) AF: 0.843 AC: 4355 AN: 5168

South Asian (SAS) AF: 0.668 AC: 3213 AN: 4812

European-Finnish (FIN) AF: 0.632 AC: 6635 AN: 10500

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.660 AC: 44831 AN: 67946

Other (OTH) AF: 0.671 AC: 1417 AN: 2112

Alfa AF: 0.677 Hom.: 4221

Bravo AF: 0.680

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jul 29, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.31
Mutation Taster		=11/89	disease causing

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: rs11377009; hg19: chr15-91346630;