15-90761191-C-G

Variant names:

• chr15-90761191-C-G
• rs1343649830
• NM_000057.4:c.1818C>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.1818C>G​(p.Asp606Glu) variant causes a missense 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. 16/22 in silico tools predict a benign outcome for this variant. 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. D606V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BLM NM_000057.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.558
• 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_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=0.046378225).

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.1818C>G	p.Asp606Glu	missense	Exon 7 of 22	NP_000048.1	P54132
	BLM	NM_001287246.2		c.1818C>G	p.Asp606Glu	missense	Exon 8 of 23	NP_001274175.1	P54132
	BLM	NM_001287247.2		c.1818C>G	p.Asp606Glu	missense	Exon 7 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.1818C>G	p.Asp606Glu	missense	Exon 7 of 22	ENSP00000347232.3	P54132
	BLM	ENST00000560509.5	TSL:1	c.1818C>G	p.Asp606Glu	missense	Exon 7 of 20	ENSP00000454158.1	H0YNU5
	BLM	ENST00000559724.5	TSL:1	n.*742C>G		non_coding_transcript_exon	Exon 7 of 22	ENSP00000453359.1	H0YLV8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000537 AC: 1 AN: 186076 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000110

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000145 AC: 2 AN: 1379600 Hom.: 0 Cov.: 31 AF XY: 0.00000147 AC XY: 1 AN XY: 678794

African (AFR) AF: 0.00 AC: 0 AN: 30414

American (AMR) AF: 0.00 AC: 0 AN: 29342

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20856

East Asian (EAS) AF: 0.00 AC: 0 AN: 39052

South Asian (SAS) AF: 0.00 AC: 0 AN: 71022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5394

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1076356

Other (OTH) AF: 0.00 AC: 0 AN: 56762

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	13
DANN	Benign	0.41
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.56
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.13
Sift	Benign	0.75	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.062
MutPred		0.17		Gain of phosphorylation at S602 (P = 0.2447)
MVP		0.58
MPC		0.083
ClinPred		0.011	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.049
gMVP		0.37
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1343649830; hg19: chr15-91304421;