rs1555418008

Variant names:

• chr15-90747449-A-G
• rs1555418008
• NM_000057.4:c.57A>G

Your query was ambiguous. Multiple possible variants found:

• chr15-90747449-A-G
• chr15-90747449-A-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_000057.4(BLM):​c.57A>G​(p.Arg19Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BLM NM_000057.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.30
• Publications: 0 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health, Genomics England PanelApp, ClinGen, Laboratory for Molecular Medicine
• 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 15-90747449-A-G is Benign according to our data. Variant chr15-90747449-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1749732.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=3.3 with no splicing effect.

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.57A>G	p.Arg19Arg	synonymous	Exon 2 of 22	NP_000048.1	P54132
	BLM	NM_001287246.2		c.57A>G	p.Arg19Arg	synonymous	Exon 3 of 23	NP_001274175.1	P54132
	BLM	NM_001287247.2		c.57A>G	p.Arg19Arg	synonymous	Exon 2 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.57A>G	p.Arg19Arg	synonymous	Exon 2 of 22	ENSP00000347232.3	P54132
	BLM	ENST00000560509.5	TSL:1	c.57A>G	p.Arg19Arg	synonymous	Exon 2 of 20	ENSP00000454158.1	H0YNU5
	BLM	ENST00000559724.5	TSL:1	n.57A>G		non_coding_transcript_exon	Exon 2 of 22	ENSP00000453359.1	H0YLV8

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458814 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725374

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25962

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 85716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110220

Other (OTH) AF: 0.00 AC: 0 AN: 60260

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.3
DANN	Benign	0.75
PhyloP100		3.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555418008; hg19: chr15-91290679;