NM_000057.4:c.1086C>G

Variant names:

• chr15-90754937-C-G
• rs375632163
• NM_000057.4:c.1086C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000057.4(BLM):​c.1086C>G​(p.Asp362Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/26 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D362D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BLM NM_000057.4 missense, splice_region
• Scores: Splicing: ADA: 0.002285
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.33
• 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04007992).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLM	NM_000057.4	c.1086C>G	p.Asp362Glu	missense_variant, splice_region_variant	Exon 5 of 22	ENST00000355112.8	NP_000048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLM	ENST00000355112.8	c.1086C>G	p.Asp362Glu	missense_variant, splice_region_variant	Exon 5 of 22	1	NM_000057.4	ENSP00000347232.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D362E variant (also known as c.1086C>G), located in coding exon 4 of the BLM gene, results from a C to G substitution at nucleotide position 1086. The aspartic acid at codon 362 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.3
DANN	Benign	0.96
DEOGEN2	Benign	0.052	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.040	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.6	L;.
PhyloP100		-3.3
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.56	N;N
REVEL	Benign	0.035
Sift	Benign	0.47	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0040	B;.
Vest4		0.12
MutPred		0.22		Gain of helix (P = 0.0225);Gain of helix (P = 0.0225);
MVP		0.45
MPC		0.085
ClinPred		0.050	T
GERP RS		-4.7
Varity_R		0.15
gMVP		0.060

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0023
dbscSNV1_RF	Benign	0.17
SpliceAI score (max)		0.57		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.57		Position offset: -5

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

Other links and lift over

dbSNP: rs375632163; hg19: chr15-91298167;