rs7167216

chr15-90811291-G-Achr15-90811291-G-C

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.3961G>A(p.Val1321Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0721 in 1,614,020 control chromosomes in the GnomAD database, including 4,643 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1321L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.079 (547 hom., cov: 32)
  • Exomes 𝑓: 0.071 (4096 hom.)
• Consequence: BLM NM_000057.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -0.636

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=0.0016637444).
• BP6: Variant 15-90811291-G-A is Benign according to our data. Variant chr15-90811291-G-A is described in ClinVar as [Benign]. Clinvar id is 128530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-90811291-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0947 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLM	NM_000057.4	c.3961G>A	p.Val1321Ile	missense_variant	21/22	ENST00000355112.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLM	ENST00000355112.8	c.3961G>A	p.Val1321Ile	missense_variant	21/22	1	NM_000057.4	P2

Frequencies

GnomAD3 genomes AF: 0.0790 AC: 12019 AN: 152054 Hom.: 545 Cov.: 32

Gnomad AFR AF: 0.0971

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.0591

Gnomad ASJ AF: 0.0302

Gnomad EAS AF: 0.0304

Gnomad SAS AF: 0.0695

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0707

Gnomad OTH AF: 0.0672

GnomAD3 exomes AF: 0.0661 AC: 16622 AN: 251418 Hom.: 675 AF XY: 0.0667 AC XY: 9066 AN XY: 135890

Gnomad AFR exome AF: 0.0946

Gnomad AMR exome AF: 0.0414

Gnomad ASJ exome AF: 0.0395

Gnomad EAS exome AF: 0.0241

Gnomad SAS exome AF: 0.0644

Gnomad FIN exome AF: 0.133

Gnomad NFE exome AF: 0.0669

Gnomad OTH exome AF: 0.0593

GnomAD4 exome AF: 0.0714 AC: 104319 AN: 1461848 Hom.: 4096 Cov.: 33 AF XY: 0.0710 AC XY: 51641 AN XY: 727226

Gnomad4 AFR exome AF: 0.0930

Gnomad4 AMR exome AF: 0.0432

Gnomad4 ASJ exome AF: 0.0372

Gnomad4 EAS exome AF: 0.0326

Gnomad4 SAS exome AF: 0.0650

Gnomad4 FIN exome AF: 0.132

Gnomad4 NFE exome AF: 0.0721

Gnomad4 OTH exome AF: 0.0675

GnomAD4 genome AF: 0.0791 AC: 12032 AN: 152172 Hom.: 547 Cov.: 32 AF XY: 0.0807 AC XY: 6001 AN XY: 74386

Gnomad4 AFR AF: 0.0972

Gnomad4 AMR AF: 0.0591

Gnomad4 ASJ AF: 0.0302

Gnomad4 EAS AF: 0.0305

Gnomad4 SAS AF: 0.0690

Gnomad4 FIN AF: 0.140

Gnomad4 NFE AF: 0.0707

Gnomad4 OTH AF: 0.0665

Alfa AF: 0.0663 Hom.: 598

Bravo AF: 0.0730

TwinsUK AF: 0.0725 AC: 269

ALSPAC AF: 0.0768 AC: 296

ESP6500AA AF: 0.0928 AC: 408

ESP6500EA AF: 0.0664 AC: 571

ExAC AF: 0.0663 AC: 8052

Asia WGS AF: 0.0440 AC: 151 AN: 3478

EpiCase AF: 0.0643

EpiControl AF: 0.0596

ClinVar

Significance: Benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bloom syndrome Benign:6

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 28, 2017	- -
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, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not specified Benign:2 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

This variant is associated with the following publications: (PMID: 24728327) -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	0.34
Dann	Benign	0.96
DEOGEN2	Benign	0.081	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.49	T;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.43	N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.43	N;N
REVEL	Benign	0.089
Sift	Benign	0.26	T;T
Sift4G	Benign	0.38	T;T
Polyphen		0.010	B;.
Vest4		0.023
MPC		0.073
ClinPred		0.0067	T
GERP RS		-4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.018
gMVP		0.11

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: rs7167216; hg19: chr15-91354521; COSMIC: COSV61921400;