rs367543029

chr15-90794311-G-Achr15-90794311-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

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. C1055R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BLM NM_000057.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 9.73

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 9 ACMG points.

• PM1: In a helix (size 3) in uniprot entity BLM_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000057.4
• 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 ClinVar as [Pathogenic]. Clinvar id is 42078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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	UniProt
BLM	NM_000057.4	c.3164G>A	p.Cys1055Tyr	missense_variant	16/22	ENST00000355112.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLM	ENST00000355112.8	c.3164G>A	p.Cys1055Tyr	missense_variant	16/22	1	NM_000057.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248860 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134496

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: 2 AN: 1453524 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722710

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.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Bloom syndrome Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	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). -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 19, 2020	- -
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	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	4.5	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
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	D
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

Other links and lift over

dbSNP: rs367543029; hg19: chr15-91337541;