NM_000057.4:c.4077-59_4077-57dupAAG

Variant names:

• chr15-90815041-G-GGAA
• rs10685387
• NM_000057.4:c.4077-59_4077-57dupAAG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000057.4(BLM):​c.4077-59_4077-57dupAAG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.632 in 1,533,884 control chromosomes in the GnomAD database, including 308,944 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31223 hom., cov: 0)
  • Exomes 𝑓: 0.63 (277721 hom.)
• Consequence: BLM NM_000057.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.130
• Publications: 4 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 -16 ACMG points.

• BP6: Variant 15-90815041-G-GGAA is Benign according to our data. Variant chr15-90815041-G-GGAA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.792 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.4077-59_4077-57dupAAG		intron	N/A	NP_000048.1
	BLM	NM_001287246.2		c.4077-59_4077-57dupAAG		intron	N/A	NP_001274175.1
	BLM	NM_001287247.2		c.3684-59_3684-57dupAAG		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.4077-59_4077-57dupAAG		intron	N/A	ENSP00000347232.3
	BLM	ENST00000560509.5	TSL:1	c.3684-59_3684-57dupAAG		intron	N/A	ENSP00000454158.1
	BLM	ENST00000559724.5	TSL:1	n.*3001-59_*3001-57dupAAG		intron	N/A	ENSP00000453359.1

Frequencies

GnomAD3 genomes AF: 0.639 AC: 96752 AN: 151496 Hom.: 31190 Cov.: 0

Gnomad AFR AF: 0.615

Gnomad AMI AF: 0.739

Gnomad AMR AF: 0.718

Gnomad ASJ AF: 0.681

Gnomad EAS AF: 0.813

Gnomad SAS AF: 0.615

Gnomad FIN AF: 0.587

Gnomad MID AF: 0.617

Gnomad NFE AF: 0.628

Gnomad OTH AF: 0.636

GnomAD4 exome AF: 0.631 AC: 871868 AN: 1382270 Hom.: 277721 AF XY: 0.629 AC XY: 435241 AN XY: 692044

African (AFR) AF: 0.627 AC: 20027 AN: 31940

American (AMR) AF: 0.769 AC: 34111 AN: 44386

Ashkenazi Jewish (ASJ) AF: 0.676 AC: 17352 AN: 25672

East Asian (EAS) AF: 0.803 AC: 31521 AN: 39276

South Asian (SAS) AF: 0.610 AC: 51450 AN: 84276

European-Finnish (FIN) AF: 0.586 AC: 26458 AN: 45144

Middle Eastern (MID) AF: 0.630 AC: 3552 AN: 5642

European-Non Finnish (NFE) AF: 0.621 AC: 650618 AN: 1048076

Other (OTH) AF: 0.636 AC: 36779 AN: 57858

GnomAD4 genome AF: 0.639 AC: 96844 AN: 151614 Hom.: 31223 Cov.: 0 AF XY: 0.638 AC XY: 47283 AN XY: 74054

African (AFR) AF: 0.615 AC: 25412 AN: 41318

American (AMR) AF: 0.718 AC: 10951 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.681 AC: 2359 AN: 3464

East Asian (EAS) AF: 0.813 AC: 4171 AN: 5132

South Asian (SAS) AF: 0.615 AC: 2963 AN: 4814

European-Finnish (FIN) AF: 0.587 AC: 6144 AN: 10472

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.629 AC: 42659 AN: 67870

Other (OTH) AF: 0.638 AC: 1342 AN: 2104

Alfa AF: 0.644 Hom.: 3360

Asia WGS AF: 0.700 AC: 2435 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Bloom syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.13
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs10685387; hg19: chr15-91358271; COSMIC: COSV61923849; COSMIC: COSV61923849;