15-90746500-A-C

Variant names:

• chr15-90746500-A-C
• rs6496724
• NM_000057.4:c.-4-889A>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.-4-889A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.357 in 152,068 control chromosomes in the GnomAD database, including 11,443 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 0.36 (11443 hom., cov: 31)
• Consequence: BLM NM_000057.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.865
• Publications: 9 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.591 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.-4-889A>C		intron	N/A	NP_000048.1
	BLM	NM_001287246.2		c.-4-889A>C		intron	N/A	NP_001274175.1
	BLM	NM_001287247.2		c.-4-889A>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.-4-889A>C		intron	N/A	ENSP00000347232.3
	BLM	ENST00000560509.5	TSL:1	c.-4-889A>C		intron	N/A	ENSP00000454158.1
	BLM	ENST00000559724.5	TSL:1	n.-4-889A>C		intron	N/A	ENSP00000453359.1

Frequencies

GnomAD3 genomes AF: 0.356 AC: 54166 AN: 151948 Hom.: 11429 Cov.: 31

Gnomad AFR AF: 0.597

Gnomad AMI AF: 0.384

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.354

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.253

Gnomad MID AF: 0.223

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.324

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

GnomAD4 genome AF: 0.357 AC: 54220 AN: 152068 Hom.: 11443 Cov.: 31 AF XY: 0.352 AC XY: 26156 AN XY: 74338

African (AFR) AF: 0.597 AC: 24757 AN: 41484

American (AMR) AF: 0.262 AC: 4010 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 832 AN: 3472

East Asian (EAS) AF: 0.354 AC: 1833 AN: 5176

South Asian (SAS) AF: 0.224 AC: 1080 AN: 4826

European-Finnish (FIN) AF: 0.253 AC: 2667 AN: 10550

Middle Eastern (MID) AF: 0.216 AC: 63 AN: 292

European-Non Finnish (NFE) AF: 0.264 AC: 17944 AN: 67970

Other (OTH) AF: 0.324 AC: 684 AN: 2108

Alfa AF: 0.341 Hom.: 1692

Bravo AF: 0.366

Asia WGS AF: 0.302 AC: 1051 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.0
DANN	Benign	0.78
PhyloP100		-0.86
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: rs6496724; hg19: chr15-91289730;