NM_000057.4:c.3210+4A>G

Variant names:

• chr15-90794361-A-G
• rs776621429
• NM_000057.4:c.3210+4A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000057.4(BLM):​c.3210+4A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000108 in 1,567,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: BLM NM_000057.4 splice_region, intron
• Scores: Splicing: ADA: 0.9347
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:2
• Conservation: PhyloP100: 3.60
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLM	NM_000057.4	MANE Select	c.3210+4A>G		splice_region intron	N/A	NP_000048.1
	BLM	NM_001287246.2		c.3210+4A>G		splice_region intron	N/A	NP_001274175.1
	BLM	NM_001287247.2		c.3210+4A>G		splice_region 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.3210+4A>G		splice_region intron	N/A	ENSP00000347232.3
	BLM	ENST00000560509.5	TSL:1	c.3210+4A>G		splice_region intron	N/A	ENSP00000454158.1
	BLM	ENST00000559724.5	TSL:1	n.*2134+4A>G		splice_region intron	N/A	ENSP00000453359.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151728 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000622 AC: 13 AN: 209104 AF XY: 0.0000263

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000496

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000106 AC: 15 AN: 1415734 Hom.: 0 Cov.: 30 AF XY: 0.00000569 AC XY: 4 AN XY: 703146

African (AFR) AF: 0.00 AC: 0 AN: 31320

American (AMR) AF: 0.000403 AC: 15 AN: 37248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24878

East Asian (EAS) AF: 0.00 AC: 0 AN: 38694

South Asian (SAS) AF: 0.00 AC: 0 AN: 76728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52032

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4946

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1091620

Other (OTH) AF: 0.00 AC: 0 AN: 58268

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151728 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74116

African (AFR) AF: 0.00 AC: 0 AN: 41262

American (AMR) AF: 0.000131 AC: 2 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67914

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	1	Bloom syndrome (5)
-	2	-	not provided (2)
-	-	1	BLM-related disorder (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Benign	0.81
PhyloP100		3.6
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.93
dbscSNV1_RF	Benign	0.66
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.36		Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs776621429; hg19: chr15-91337591;