15-90813274-T-C

Variant names:

• chr15-90813274-T-C
• rs401549
• NM_000057.4:c.4077-1828T>C

Variant summary

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

The NM_000057.4(BLM):​c.4077-1828T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 152,206 control chromosomes in the GnomAD database, including 8,819 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 0.32 (8819 hom., cov: 33)
• Consequence: BLM NM_000057.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0110
• Publications: 21 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

ENSG00000287061 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.538 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLM	NM_000057.4	MANE Select	c.4077-1828T>C		intron	N/A	NP_000048.1
	BLM	NM_001287246.2		c.4077-1828T>C		intron	N/A	NP_001274175.1
	BLM	NM_001287247.2		c.3684-1828T>C		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.4077-1828T>C		intron	N/A	ENSP00000347232.3
	BLM	ENST00000560509.5	TSL:1	c.3684-1828T>C		intron	N/A	ENSP00000454158.1
	BLM	ENST00000559724.5	TSL:1	n.*3001-1828T>C		intron	N/A	ENSP00000453359.1

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48654 AN: 152088 Hom.: 8821 Cov.: 33

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.467

Gnomad ASJ AF: 0.404

Gnomad EAS AF: 0.555

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.331

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

GnomAD4 genome AF: 0.320 AC: 48676 AN: 152206 Hom.: 8819 Cov.: 33 AF XY: 0.326 AC XY: 24261 AN XY: 74422

African (AFR) AF: 0.150 AC: 6220 AN: 41552

American (AMR) AF: 0.467 AC: 7139 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.404 AC: 1403 AN: 3470

East Asian (EAS) AF: 0.555 AC: 2874 AN: 5182

South Asian (SAS) AF: 0.429 AC: 2068 AN: 4822

European-Finnish (FIN) AF: 0.349 AC: 3699 AN: 10596

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.353 AC: 24023 AN: 67992

Other (OTH) AF: 0.332 AC: 700 AN: 2108

Alfa AF: 0.351 Hom.: 17716

Bravo AF: 0.323

Asia WGS AF: 0.450 AC: 1563 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.3
DANN	Benign	0.71
PhyloP100		-0.011
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: rs401549; hg19: chr15-91356504;