rs141503266

chr15-90749522-G-Cchr15-90749522-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000057.4(BLM):c.254G>C(p.Arg85Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000359 in 1,614,124 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R85K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: BLM NM_000057.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -0.410

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 -18 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0031244755).
• BP6: Variant 15-90749522-G-C is Benign according to our data. Variant chr15-90749522-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 127488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-90749522-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00198 (302/152268) while in subpopulation AFR AF= 0.00671 (279/41554). AF 95% confidence interval is 0.00607. There are 0 homozygotes in gnomad4. There are 146 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLM	NM_000057.4	c.254G>C	p.Arg85Thr	missense_variant	3/22	ENST00000355112.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLM	ENST00000355112.8	c.254G>C	p.Arg85Thr	missense_variant	3/22	1	NM_000057.4	P2

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 302 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00673

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000505 AC: 127 AN: 251336 Hom.: 2 AF XY: 0.000420 AC XY: 57 AN XY: 135868

Gnomad AFR exome AF: 0.00622

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000189 AC: 277 AN: 1461856 Hom.: 1 Cov.: 31 AF XY: 0.000160 AC XY: 116 AN XY: 727226

Gnomad4 AFR exome AF: 0.00654

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.00198 AC: 302 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.00196 AC XY: 146 AN XY: 74436

Gnomad4 AFR AF: 0.00671

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000327 Hom.: 0

Bravo AF: 0.00209

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000560 AC: 68

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 17, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 30, 2017	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 18, 2023	Variant summary: BLM c.254G>C (p.Arg85Thr) results in a non-conservative amino acid change located in the RecQ-like DNA helicase BLM, N-terminal domain (IPR032437) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00051 in 251336 control chromosomes, predominantly at a frequency of 0.0062 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in BLM causing Bloom Syndrome phenotype (0.0035), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.254G>C has been reported in the literature in patients who underwent hereditary multigene panel testing for breast cancer, however authors classified the variant as VUS (example: Guindalini_2022). This report does not provide unequivocal conclusions about association of the variant with Bloom Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 35264596). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Bloom syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 02, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 28, 2019	This alteration is classified as likely 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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 12, 2021	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 08, 2022

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	0.19
Dann	Benign	0.33
DEOGEN2	Benign	0.058	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.62	T;T
MetaRNN	Benign	0.0031	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.26	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.37	N;N
REVEL	Benign	0.017
Sift	Benign	0.27	T;T
Sift4G	Benign	0.57	T;T
Polyphen		0.0020	B;.
Vest4		0.13
MVP		0.49
MPC		0.13
ClinPred		0.000093	T
GERP RS		-3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.027
gMVP		0.080

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs141503266; hg19: chr15-91292752; COSMIC: COSV104422197; COSMIC: COSV104422197;