rs367543029

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

The NM_000057.4(BLM):c.3164G>A(p.Cys1055Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,453,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1055S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BLM
NM_000057.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: 9.73

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 links:

BLM (HGNC:):

BLM links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity BLM_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-90794311-G-C is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.892

PP5

Variant 15-90794311-G-A is Pathogenic according to our data. Variant chr15-90794311-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 803137.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BLM	NM_000057.4 linkuse as main transcript	c.3164G>A	p.Cys1055Tyr	missense_variant	16/22	ENST00000355112.8	NP_000048.1	P54132

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BLM	ENST00000355112.8 linkuse as main transcript	c.3164G>A	p.Cys1055Tyr	missense_variant	16/22	1	NM_000057.4	ENSP00000347232.3		P54132

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248860

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134496

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000996

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1453524

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722710

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Bloom syndrome

Pathogenic:1Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 19, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 20, 2022	This variant is present in population databases (no rsID available, gnomAD 0.01%). 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. This variant disrupts the p.Cys1055 amino acid residue in BLM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7585968, 9840919, 10069810, 11399766, 17407155, 28877996). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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"). ClinVar contains an entry for this variant (Variation ID: 803137). This variant has not been reported in the literature in individuals affected with BLM-related conditions. This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1055 of the BLM protein (p.Cys1055Tyr). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 12, 2020

The p.C1055Y variant (also known as c.3164G>A), located in coding exon 15 of the BLM gene, results from a G to A substitution at nucleotide position 3164. The cysteine at codon 1055 is replaced by tyrosine, an amino acid with highly dissimilar properties. Based on internal structural analysis, p.C1055Y is strongly disruptive to the structure of the zinc-binding domain of BLM, and abrogates an interaction with the zinc ion at position with known pathogenic variants (Guo RB et al. Nucleic Acids Res., 2005 Jun;33:3109-24; Swan MK et al. Acta Crystallogr. D Biol. Crystallogr., 2014 May;70:1465-75; Newman JA et al. Nucleic Acids Res., 2015 May;43:5221-35). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). A different alteration at this position, p.C1055G, has been found in one patient with Bloom syndrome who also has an Ashkenazi Jewish founder mutation (German J et al. Hum. Mutat., 2007 Aug;28:743-53; Shastri VM et al. Mol Genet Genomic Med, 2016 Jan;4:106-19). A second alteration at this position, p.C1055S, has been reported in the literature in both a homozygous and compound heterozygous state in individuals with Bloom syndrome (Ellis NA et al. Cell, 1995 Nov;83:655-66; German J et al. Hum. Mutat., 2007 Aug;28:743-53) and functional studies have demonstrated that p.C1055S causes reduced BLM protein expression and lacks detectable helicase and DNA-dependent ATPase activities, which are essential for wild-type interaction of BLM with tp53 in the DNA damage response pathway (Wang XW et al. J. Biol. Chem., 2001 Aug;276:32948-55; Neff NF et al. Mol. Biol. Cell, 1999 Mar;10:665-76). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Jan 20, 2023

The frequency of this variant in the general population, 0.000004 (1/248860 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported to cause structural disruption and result in loss of Zinc binding using computational tools (PMID: 32704157 (2020)). Other variants at this amino acid position have also been reported to be damaging to protein function (PMID: 15930159 (2005)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.89

D;D

MetaSVM

Uncertain

0.75

MutationAssessor

Pathogenic

4.5

H;.

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-11

D;D

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0020

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.89

MutPred

0.61

Loss of methylation at K1056 (P = 0.02);Loss of methylation at K1056 (P = 0.02);

MVP

0.95

MPC

0.62

ClinPred

1.0

GERP RS

5.8

Varity_R

0.99

gMVP

0.89

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over