rs28385011

Variant names:

• chr15-90761095-A-G
• rs28385011
• NM_000057.4:c.1722A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000057.4(BLM):​c.1722A>G​(p.Leu574Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00609 in 1,550,562 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L574L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0045 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (73 hom.)
• Consequence: BLM NM_000057.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.378
• 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: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, Laboratory for Molecular Medicine, Orphanet, Myriad Women’s Health
• osteosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• colorectal cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 15-90761095-A-G is Benign according to our data. Variant chr15-90761095-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.378 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00447 (681/152288) while in subpopulation SAS AF = 0.0245 (118/4818). AF 95% confidence interval is 0.0209. There are 5 homozygotes in GnomAd4. There are 345 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,AD gene

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.1722A>G	p.Leu574Leu	synonymous	Exon 7 of 22	NP_000048.1	P54132
	BLM	NM_001287246.2		c.1722A>G	p.Leu574Leu	synonymous	Exon 8 of 23	NP_001274175.1	P54132
	BLM	NM_001287247.2		c.1722A>G	p.Leu574Leu	synonymous	Exon 7 of 20	NP_001274176.1	H0YNU5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLM	ENST00000355112.8	TSL:1 MANE Select	c.1722A>G	p.Leu574Leu	synonymous	Exon 7 of 22	ENSP00000347232.3	P54132
	BLM	ENST00000560509.5	TSL:1	c.1722A>G	p.Leu574Leu	synonymous	Exon 7 of 20	ENSP00000454158.1	H0YNU5
	BLM	ENST00000559724.5	TSL:1	n.*646A>G		non_coding_transcript_exon	Exon 7 of 22	ENSP00000453359.1	H0YLV8

Frequencies

GnomAD3 genomes AF: 0.00447 AC: 680 AN: 152170 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0243

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00585

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00631 AC: 1244 AN: 196992 AF XY: 0.00716

Gnomad AFR exome AF: 0.000966

Gnomad AMR exome AF: 0.00196

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.0000618

Gnomad FIN exome AF: 0.00450

Gnomad NFE exome AF: 0.00581

Gnomad OTH exome AF: 0.00547

GnomAD4 exome AF: 0.00627 AC: 8769 AN: 1398274 Hom.: 73 Cov.: 31 AF XY: 0.00679 AC XY: 4687 AN XY: 690048

African (AFR) AF: 0.00120 AC: 37 AN: 30896

American (AMR) AF: 0.00193 AC: 64 AN: 33150

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 203 AN: 22020

East Asian (EAS) AF: 0.0000509 AC: 2 AN: 39266

South Asian (SAS) AF: 0.0244 AC: 1804 AN: 73876

European-Finnish (FIN) AF: 0.00488 AC: 248 AN: 50768

Middle Eastern (MID) AF: 0.00737 AC: 40 AN: 5428

European-Non Finnish (NFE) AF: 0.00556 AC: 6029 AN: 1085276

Other (OTH) AF: 0.00594 AC: 342 AN: 57594

GnomAD4 genome AF: 0.00447 AC: 681 AN: 152288 Hom.: 5 Cov.: 32 AF XY: 0.00463 AC XY: 345 AN XY: 74470

African (AFR) AF: 0.000722 AC: 30 AN: 41572

American (AMR) AF: 0.00366 AC: 56 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 34 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.0245 AC: 118 AN: 4818

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00585 AC: 398 AN: 68016

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00499 Hom.: 3

Bravo AF: 0.00360

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Bloom syndrome (6)
-	-	5	not specified (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	-0.82
CADD	Benign	6.9
DANN	Benign	0.70
PhyloP100		0.38
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs28385011; hg19: chr15-91304325; COSMIC: COSV61924631; COSMIC: COSV61924631;