Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_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

Variant links:

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

BLM links:

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ACMG classification

Classification was made for transcript

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).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BLM	NM_000057.4	MANE Select	c.1086C>G	p.Asp362Glu	missense splice_region	Exon 5 of 22	NP_000048.1
BLM	NM_001287246.2		c.1086C>G	p.Asp362Glu	missense splice_region	Exon 6 of 23	NP_001274175.1
BLM	NM_001287247.2		c.1086C>G	p.Asp362Glu	missense splice_region	Exon 5 of 20	NP_001274176.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BLM	ENST00000355112.8	TSL:1 MANE Select	c.1086C>G	p.Asp362Glu	missense splice_region	Exon 5 of 22	ENSP00000347232.3
BLM	ENST00000560509.5	TSL:1	c.1086C>G	p.Asp362Glu	missense splice_region	Exon 5 of 20	ENSP00000454158.1
BLM	ENST00000559724.5	TSL:1	n.1086C>G		splice_region non_coding_transcript_exon	Exon 5 of 22	ENSP00000453359.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

4.3

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.052

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.59

M_CAP

Benign

0.0088

MetaRNN

Benign

0.040

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.6

PhyloP100

-3.3

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.56

REVEL

Benign

0.035

Sift

Benign

0.47

Sift4G

Benign

1.0

Polyphen

0.0040

Vest4

0.12

MutPred

0.22

Gain of helix (P = 0.0225)

MVP

0.45

MPC

0.085

ClinPred

0.050

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

Publications

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rs375632163

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over