rs28384991

chr15-90751880-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000057.4(BLM):c.893C>T(p.Thr298Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00365 in 1,612,942 control chromosomes in the GnomAD database, including 234 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T298T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0048 (27 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (207 hom.)
• Consequence: BLM NM_000057.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: 0.504

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012453198).
• BP6: Variant 15-90751880-C-T is Benign according to our data. Variant chr15-90751880-C-T is described in ClinVar as [Benign]. Clinvar id is 92397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-90751880-C-T is described in Lovd as [Benign]. Variant chr15-90751880-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0847 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLM	NM_000057.4	c.893C>T	p.Thr298Met	missense_variant	4/22	ENST00000355112.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLM	ENST00000355112.8	c.893C>T	p.Thr298Met	missense_variant	4/22	1	NM_000057.4	P2

Frequencies

GnomAD3 genomes AF: 0.00482 AC: 733 AN: 152136 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0915

Gnomad SAS AF: 0.00601

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00982 AC: 2467 AN: 251256 Hom.: 107 AF XY: 0.00866 AC XY: 1176 AN XY: 135804

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.0168

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0969

Gnomad SAS exome AF: 0.00160

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00571

GnomAD4 exome AF: 0.00353 AC: 5157 AN: 1460688 Hom.: 207 Cov.: 31 AF XY: 0.00340 AC XY: 2469 AN XY: 726730

Gnomad4 AFR exome AF: 0.000628

Gnomad4 AMR exome AF: 0.0173

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0948

Gnomad4 SAS exome AF: 0.00218

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.00631

GnomAD4 genome AF: 0.00483 AC: 735 AN: 152254 Hom.: 27 Cov.: 32 AF XY: 0.00498 AC XY: 371 AN XY: 74454

Gnomad4 AFR AF: 0.00103

Gnomad4 AMR AF: 0.0112

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0915

Gnomad4 SAS AF: 0.00581

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00711

Alfa AF: 0.00317 Hom.: 33

Bravo AF: 0.00577

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00858 AC: 1042

Asia WGS AF: 0.0330 AC: 114 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bloom syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 25, 2017	- -

not specified Benign:4 Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 01, 2013	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 21, 2021	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 31, 2016	Variant summary: The BLM c.893C>T (p.Thr298Met) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1165/122686 control chromosomes (43 homozygotes), predominantly observed in the East Asian subpopulation at a frequency of 0.0901317 (780/8654). This frequency is about 25 times the estimated maximal expected allele frequency of a pathogenic BLM variant (0.0035355), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. Additionally, the variant has been reported at the same frequency in control and affected populations, further evidence that this variant is benign (Sakiyama_IJC_2005). One clinical diagnostic laboratory/reputable database has classified this variant as benign. Taken together and based on the high allele frequency in the general population, this variant was classified as benign. -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 24728327, 27876123) -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 18, 2016	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 06, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	15
Dann	Benign	0.89
DEOGEN2	Benign	0.046	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0014	N
LIST_S2	Benign	0.56	T;T
MetaRNN	Benign	0.0012	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.35	N;N
REVEL	Benign	0.022
Sift	Benign	0.19	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.0	B;.
Vest4		0.069
MVP		0.53
MPC		0.092
ClinPred		0.00068	T
GERP RS		0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.012
gMVP		0.076

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: rs28384991; hg19: chr15-91295110; COSMIC: COSV61922716; COSMIC: COSV61922716;