rs1555420546

Variant names:

• chr15-90766910-A-T
• rs1555420546
• NM_000057.4:c.2194A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000057.4(BLM):​c.2194A>T​(p.Ile732Phe) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,415,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I732M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: BLM NM_000057.4 missense, splice_region
• Scores: Splicing: ADA: 0.6589
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 8.55
• 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: 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 29 uncertain in NM_000057.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLM	NM_000057.4	MANE Select	c.2194A>T	p.Ile732Phe	missense splice_region	Exon 10 of 22	NP_000048.1
	BLM	NM_001287246.2		c.2194A>T	p.Ile732Phe	missense splice_region	Exon 11 of 23	NP_001274175.1
	BLM	NM_001287247.2		c.2194A>T	p.Ile732Phe	missense splice_region	Exon 10 of 20	NP_001274176.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLM	ENST00000355112.8	TSL:1 MANE Select	c.2194A>T	p.Ile732Phe	missense splice_region	Exon 10 of 22	ENSP00000347232.3
	BLM	ENST00000560509.5	TSL:1	c.2194A>T	p.Ile732Phe	missense splice_region	Exon 10 of 20	ENSP00000454158.1
	BLM	ENST00000559724.5	TSL:1	n.*1118A>T		splice_region non_coding_transcript_exon	Exon 10 of 22	ENSP00000453359.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1415090 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 706242

African (AFR) AF: 0.00 AC: 0 AN: 32402

American (AMR) AF: 0.00 AC: 0 AN: 44398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25804

East Asian (EAS) AF: 0.00 AC: 0 AN: 39284

South Asian (SAS) AF: 0.00 AC: 0 AN: 84446

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5682

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1070916

Other (OTH) AF: 0.0000170 AC: 1 AN: 58832

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Bloom syndrome (2)
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.062	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		8.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.039	D
Polyphen		0.99	D
Vest4		0.97
MutPred		0.56		Gain of catalytic residue at I732 (P = 0.0229)
MVP		0.89
MPC		0.57
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.75
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.66
dbscSNV1_RF	Benign	0.52
SpliceAI score (max)		0.030		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: rs1555420546; hg19: chr15-91310140;