NM_000057.4:c.2074+1023C>G

Variant names:

• chr15-90764180-C-G
• rs2518968
• NM_000057.4:c.2074+1023C>G

Variant summary

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

The NM_000057.4(BLM):​c.2074+1023C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.52 in 149,464 control chromosomes in the GnomAD database, including 20,467 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 0.52 (20467 hom., cov: 28)
• Consequence: BLM NM_000057.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0180
• 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.547 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLM	NM_000057.4	c.2074+1023C>G		intron_variant	Intron 8 of 21	ENST00000355112.8	NP_000048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLM	ENST00000355112.8	c.2074+1023C>G		intron_variant	Intron 8 of 21	1	NM_000057.4	ENSP00000347232.3

Frequencies

GnomAD3 genomes AF: 0.520 AC: 77648 AN: 149414 Hom.: 20461 Cov.: 28

Gnomad AFR AF: 0.523

Gnomad AMI AF: 0.386

Gnomad AMR AF: 0.426

Gnomad ASJ AF: 0.471

Gnomad EAS AF: 0.379

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.416

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.501

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

GnomAD4 genome AF: 0.520 AC: 77671 AN: 149464 Hom.: 20467 Cov.: 28 AF XY: 0.515 AC XY: 37474 AN XY: 72776

African (AFR) AF: 0.523 AC: 21306 AN: 40710

American (AMR) AF: 0.426 AC: 6381 AN: 14982

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 1631 AN: 3464

East Asian (EAS) AF: 0.380 AC: 1953 AN: 5134

South Asian (SAS) AF: 0.487 AC: 2316 AN: 4758

European-Finnish (FIN) AF: 0.554 AC: 5312 AN: 9582

Middle Eastern (MID) AF: 0.413 AC: 118 AN: 286

European-Non Finnish (NFE) AF: 0.551 AC: 37261 AN: 67564

Other (OTH) AF: 0.502 AC: 1044 AN: 2080

Alfa AF: 0.432 Hom.: 1277

Bravo AF: 0.506

Asia WGS AF: 0.453 AC: 1578 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	6.3
DANN	Benign	0.72
PhyloP100		-0.018
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: rs2518968; hg19: chr15-91307410;