15-90780040-C-T

Variant names:

• chr15-90780040-C-T
• rs8037430
• NM_000057.4:c.2556-2782C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000355112.8(BLM):​c.2556-2782C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 150,080 control chromosomes in the GnomAD database, including 9,977 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.35 (9977 hom., cov: 30)
• Consequence: BLM ENST00000355112.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0680
• Publications: 14 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000355112.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLM	NM_000057.4	MANE Select	c.2556-2782C>T		intron	N/A	NP_000048.1
	BLM	NM_001287246.2		c.2556-2782C>T		intron	N/A	NP_001274175.1
	BLM	NM_001287247.2		c.2556-2782C>T		intron	N/A	NP_001274176.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLM	ENST00000355112.8	TSL:1 MANE Select	c.2556-2782C>T		intron	N/A	ENSP00000347232.3
	BLM	ENST00000560509.5	TSL:1	c.2556-2782C>T		intron	N/A	ENSP00000454158.1
	BLM	ENST00000559724.5	TSL:1	n.*1480-2782C>T		intron	N/A	ENSP00000453359.1

Frequencies

GnomAD3 genomes AF: 0.350 AC: 52491 AN: 150006 Hom.: 9956 Cov.: 30

Gnomad AFR AF: 0.509

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.210

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.245

Gnomad NFE AF: 0.310

Gnomad OTH AF: 0.311

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.350 AC: 52556 AN: 150080 Hom.: 9977 Cov.: 30 AF XY: 0.344 AC XY: 25134 AN XY: 73092

African (AFR) AF: 0.510 AC: 20852 AN: 40902

American (AMR) AF: 0.238 AC: 3579 AN: 15030

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 833 AN: 3452

East Asian (EAS) AF: 0.211 AC: 1077 AN: 5106

South Asian (SAS) AF: 0.189 AC: 893 AN: 4720

European-Finnish (FIN) AF: 0.339 AC: 3353 AN: 9902

Middle Eastern (MID) AF: 0.241 AC: 69 AN: 286

European-Non Finnish (NFE) AF: 0.310 AC: 21001 AN: 67698

Other (OTH) AF: 0.311 AC: 648 AN: 2084

Alfa AF: 0.298 Hom.: 11734

Bravo AF: 0.348

Asia WGS AF: 0.212 AC: 739 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	2.1
DANN	Benign	0.63
PhyloP100		-0.068
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: rs8037430; hg19: chr15-91323270;