rs763471784

chr15-90784930-G-Achr15-90784930-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000057.4(BLM):c.2672G>A(p.Gly891Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. G891R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BLM NM_000057.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.88

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLM	NM_000057.4	c.2672G>A	p.Gly891Glu	missense_variant	14/22	ENST00000355112.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLM	ENST00000355112.8	c.2672G>A	p.Gly891Glu	missense_variant	14/22	1	NM_000057.4	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bloom syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 09, 2022

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 891 of the BLM protein (p.Gly891Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Bloom syndrome (PMID: 17407155). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 524780). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects BLM function (PMID: 17878217). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 17, 2023

The p.G891E variant (also known as c.2672G>A), located in coding exon 13 of the BLM gene, results from a G to A substitution at nucleotide position 2672. The glycine at codon 891 is replaced by glutamic acid, an amino acid with similar properties. This variant was observed in a compound heterozygous individual affected with Bloom Syndrome (German J et al. Hum. Mutat., 2007 Aug;28:743-53). Structural modeling of the p.G891E variant on the BLM helicase domain predicts that this variant will abolish both ATPase and DNA unwinding activities of BLM protein (Rong SB et al. Mol. Med., 2000 Mar;6:155-64). An in-depth in vitro analysis for BLM function in this variant showed a strong reduction in helicase, ATPase, and DNA binding activities, but no deficiency in ATP binding (Guo RB et al. Nucleic Acids Res., 2007 Sep;35:6297-310). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	4.5	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.8	D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		1.0
MVP		0.97
MPC		0.54
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.99
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs763471784; hg19: chr15-91328160;