rs4932363

Variant names:

• chr15-90779871-G-A
• rs4932363
• NM_000057.4:c.2556-2951G>A

Variant summary

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

The NM_000057.4(BLM):​c.2556-2951G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0377 in 152,060 control chromosomes in the GnomAD database, including 144 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 0.038 (144 hom., cov: 32)
• Consequence: BLM NM_000057.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.146
• Publications: 7 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=-0.76).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0528 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000057.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLM	NM_000057.4	MANE Select	c.2556-2951G>A		intron	N/A	NP_000048.1
	BLM	NM_001287246.2		c.2556-2951G>A		intron	N/A	NP_001274175.1
	BLM	NM_001287247.2		c.2556-2951G>A		intron	N/A	NP_001274176.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLM	ENST00000355112.8	TSL:1 MANE Select	c.2556-2951G>A		intron	N/A	ENSP00000347232.3
	BLM	ENST00000560509.5	TSL:1	c.2556-2951G>A		intron	N/A	ENSP00000454158.1
	BLM	ENST00000559724.5	TSL:1	n.*1480-2951G>A		intron	N/A	ENSP00000453359.1

Frequencies

GnomAD3 genomes AF: 0.0377 AC: 5730 AN: 151942 Hom.: 144 Cov.: 32

Gnomad AFR AF: 0.00948

Gnomad AMI AF: 0.0736

Gnomad AMR AF: 0.0368

Gnomad ASJ AF: 0.0389

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.0667

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.0543

Gnomad OTH AF: 0.0455

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

GnomAD4 genome AF: 0.0377 AC: 5727 AN: 152060 Hom.: 144 Cov.: 32 AF XY: 0.0368 AC XY: 2736 AN XY: 74300

African (AFR) AF: 0.00945 AC: 392 AN: 41494

American (AMR) AF: 0.0367 AC: 561 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0389 AC: 135 AN: 3466

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5178

South Asian (SAS) AF: 0.0139 AC: 67 AN: 4808

European-Finnish (FIN) AF: 0.0667 AC: 704 AN: 10552

Middle Eastern (MID) AF: 0.0445 AC: 13 AN: 292

European-Non Finnish (NFE) AF: 0.0543 AC: 3690 AN: 67968

Other (OTH) AF: 0.0445 AC: 94 AN: 2110

Alfa AF: 0.0446 Hom.: 124

Bravo AF: 0.0352

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	9.6
DANN	Benign	0.87
PhyloP100		0.15
Mutation Taster		=100/0	polymorphism

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: rs4932363; hg19: chr15-91323101;