rs28903082

Variant names:

• chr15-90749883-G-A
• rs28903082
• NM_000057.4:c.615G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-90749883-G-A
• chr15-90749883-G-C
• chr15-90749883-G-T

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.615G>A​(p.Lys205Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000863 in 1,611,530 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (2 hom.)
• Consequence: BLM NM_000057.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.14
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 15-90749883-G-A is Benign according to our data. Variant chr15-90749883-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.14 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00448 (682/152266) while in subpopulation AFR AF = 0.0156 (648/41548). AF 95% confidence interval is 0.0146. There are 7 homozygotes in GnomAd4. There are 312 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.615G>A	p.Lys205Lys	synonymous	Exon 3 of 22	NP_000048.1
	BLM	NM_001287246.2		c.615G>A	p.Lys205Lys	synonymous	Exon 4 of 23	NP_001274175.1
	BLM	NM_001287247.2		c.615G>A	p.Lys205Lys	synonymous	Exon 3 of 20	NP_001274176.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLM	ENST00000355112.8	TSL:1 MANE Select	c.615G>A	p.Lys205Lys	synonymous	Exon 3 of 22	ENSP00000347232.3
	BLM	ENST00000560509.5	TSL:1	c.615G>A	p.Lys205Lys	synonymous	Exon 3 of 20	ENSP00000454158.1
	BLM	ENST00000559724.5	TSL:1	n.615G>A		non_coding_transcript_exon	Exon 3 of 22	ENSP00000453359.1

Frequencies

GnomAD3 genomes AF: 0.00450 AC: 684 AN: 152148 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00128 AC: 320 AN: 250338 AF XY: 0.000768

Gnomad AFR exome AF: 0.0176

Gnomad AMR exome AF: 0.000698

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000485 AC: 708 AN: 1459264 Hom.: 2 Cov.: 31 AF XY: 0.000396 AC XY: 287 AN XY: 725500

African (AFR) AF: 0.0177 AC: 589 AN: 33340

American (AMR) AF: 0.000629 AC: 28 AN: 44500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.000869 AC: 5 AN: 5756

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1110186

Other (OTH) AF: 0.00101 AC: 61 AN: 60294

GnomAD4 genome AF: 0.00448 AC: 682 AN: 152266 Hom.: 7 Cov.: 32 AF XY: 0.00419 AC XY: 312 AN XY: 74442

African (AFR) AF: 0.0156 AC: 648 AN: 41548

American (AMR) AF: 0.00177 AC: 27 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68006

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

Alfa AF: 0.00267 Hom.: 1

Bravo AF: 0.00494

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Bloom syndrome (3)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.7
DANN	Benign	0.60
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs28903082; hg19: chr15-91293113;