rs139282091

Variant names:

• chr15-90747490-C-G
• rs139282091
• NM_000057.4:c.98C>G

Your query was ambiguous. Multiple possible variants found:

• chr15-90747490-C-G
• chr15-90747490-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001287248.2(BLM):​c.-1194C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BLM NM_001287248.2 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.0001499
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.367
• 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.625

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001287248.2. 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.98C>G	p.Ser33*	stop_gained splice_region	Exon 2 of 22	NP_000048.1	P54132
	BLM	NM_001287248.2		c.-1194C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 22	NP_001274177.1
	BLM	NM_001287246.2		c.98C>G	p.Ser33*	stop_gained splice_region	Exon 3 of 23	NP_001274175.1	P54132

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLM	ENST00000355112.8	TSL:1 MANE Select	c.98C>G	p.Ser33*	stop_gained splice_region	Exon 2 of 22	ENSP00000347232.3	P54132
	BLM	ENST00000560509.5	TSL:1	c.98C>G	p.Ser33*	stop_gained splice_region	Exon 2 of 20	ENSP00000454158.1	H0YNU5
	BLM	ENST00000559724.5	TSL:1	n.98C>G		splice_region non_coding_transcript_exon	Exon 2 of 22	ENSP00000453359.1	H0YLV8

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	33
DANN	Uncertain	0.98
Eigen	Uncertain	0.41
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.36	N
M_CAP	Benign	0.013	T
PhyloP100		-0.37
Vest4		0.74
GERP RS		2.7
Mutation Taster		=2/198	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.42
SpliceAI score (max)		0.0		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: rs139282091; hg19: chr15-91290720;