rs7167216

Variant names:

• chr15-90811291-G-A
• rs7167216
• NM_000057.4:c.3961G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-90811291-G-A
• chr15-90811291-G-C
• chr15-90811291-G-T

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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:11 O:1
• Conservation: PhyloP100: -0.636
• Publications: 34 publications found

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 Gene-Disease associations (from GenCC):

• Bloom syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Orphanet, Genomics England PanelApp, ClinGen
• osteosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ENSG00000287061 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 128530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
BLM	NM_000057.4	c.3961G>A	p.Val1321Ile	missense_variant	Exon 21 of 22	ENST00000355112.8	NP_000048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLM	ENST00000355112.8	c.3961G>A	p.Val1321Ile	missense_variant	Exon 21 of 22	1	NM_000057.4	ENSP00000347232.3

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

GnomAD2 exomes AF: 0.0661 AC: 16622 AN: 251418 AF XY: 0.0667

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 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

African (AFR) AF: 0.0930 AC: 3112 AN: 33480

American (AMR) AF: 0.0432 AC: 1930 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0372 AC: 973 AN: 26136

East Asian (EAS) AF: 0.0326 AC: 1293 AN: 39700

South Asian (SAS) AF: 0.0650 AC: 5610 AN: 86256

European-Finnish (FIN) AF: 0.132 AC: 7025 AN: 53414

Middle Eastern (MID) AF: 0.0307 AC: 177 AN: 5766

European-Non Finnish (NFE) AF: 0.0721 AC: 80125 AN: 1111982

Other (OTH) AF: 0.0675 AC: 4074 AN: 60390

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

African (AFR) AF: 0.0972 AC: 4035 AN: 41516

American (AMR) AF: 0.0591 AC: 904 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0302 AC: 105 AN: 3472

East Asian (EAS) AF: 0.0305 AC: 158 AN: 5182

South Asian (SAS) AF: 0.0690 AC: 333 AN: 4828

European-Finnish (FIN) AF: 0.140 AC: 1482 AN: 10562

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0707 AC: 4808 AN: 68012

Other (OTH) AF: 0.0665 AC: 140 AN: 2106

Alfa AF: 0.0682 Hom.: 1056

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:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bloom syndrome Benign:6

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2 Other:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hereditary cancer-predisposing syndrome Benign:1

Aug 12, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.
PhyloP100		-0.64
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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7167216; hg19: chr15-91354521;