chr15-90766923-ATCTGA-TAGATTC

Variant names:

• chr15-90766923-ATCTGA-TAGATTC
• rs113993962
• NM_000057.4:c.2207_2212delATCTGAinsTAGATTC

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000057.4(BLM):​c.2207_2212delATCTGAinsTAGATTC​(p.Tyr736LeufsTer5) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000245583: "In vitro functional studies also provide some evidence that the p.Tyr736LeufsX5 variant may impact protein function (Ellis 1995)."" and additional evidence is available in ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BLM NM_000057.4 frameshift, missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21 U:1 O:2
• Conservation: PhyloP100: 7.36
• Publications: 11 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: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000245583: "In vitro functional studies also provide some evidence that the p.Tyr736LeufsX5 variant may impact protein function (Ellis 1995)."; SCV000694477: Skin fibroblast cell lines established from a person who was homozygous for this variant (GM08505) exhibit a spontaneous, approximately 10-fold increase in the frequency of SCEs (sister chromatid exchanges) compared to cells from unaffected persons. They also present with quadriradial chromosomes in metaphase spreads, are hypersensitive to genotoxic agent hydroxyurea, and show a delay in activating the DNA damage response after exposure to the topoisomerase poison CPT (Shastri_2015).; SCV000915701: Ellis et al. (1999) report that a SV40-transformed fibroblast cell line, derived from a skin biopsy sample obtained from an individual homozygous for the p.Tyr736LeufsTer5 variant was effectively null for the BLM protein.; SCV006311246: A functional study showed that this alteration did not create BLM protein (PMID:10521302).; SCV005361674: Functional studies utilizing cells derived from a skin biopsy obtained from an individual homozygous for the c.2207_2212delATCTGAinsTAGATTC (p.Tyr736LeufsTer5) variant showed the variant did not create BLM protein (Ellis et al. 1999. PubMed ID: 10521302).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-90766923-ATCTGA-TAGATTC is Pathogenic according to our data. Variant chr15-90766923-ATCTGA-TAGATTC is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2207_2212delATCTGAinsTAGATTC	p.Tyr736LeufsTer5	frameshift missense	Exon 10 of 22	NP_000048.1	P54132
	BLM	NM_001287246.2		c.2207_2212delATCTGAinsTAGATTC	p.Tyr736LeufsTer5	frameshift missense	Exon 11 of 23	NP_001274175.1	P54132
	BLM	NM_001287247.2		c.2207_2212delATCTGAinsTAGATTC	p.Tyr736LeufsTer5	frameshift missense	Exon 10 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.2207_2212delATCTGAinsTAGATTC	p.Tyr736LeufsTer5	frameshift missense	Exon 10 of 22	ENSP00000347232.3	P54132
	BLM	ENST00000560509.5	TSL:1	c.2207_2212delATCTGAinsTAGATTC	p.Tyr736LeufsTer5	frameshift missense	Exon 10 of 20	ENSP00000454158.1	H0YNU5
	BLM	ENST00000559724.5	TSL:1	n.*1131_*1136delATCTGAinsTAGATTC		non_coding_transcript_exon	Exon 10 of 22	ENSP00000453359.1	H0YLV8

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
11	-	-	Bloom syndrome (12)
7	-	-	not provided (8)
2	1	-	Hereditary cancer-predisposing syndrome (3)
1	-	-	BLM-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.4
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs113993962; hg19: chr15-91310153;