Variant 8-89955483-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002485.5(NBN):c.1197T>C(p.Asp399=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 1,612,850 control chromosomes in the GnomAD database, including 145,187 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.51 ( 22042 hom., cov: 31)

Exomes 𝑓: 0.40 ( 123145 hom. )

Consequence

NBN
NM_002485.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: -0.0610

Variant links:

Genes affected

NBN (HGNC:7652): (nibrin) Mutations in this gene are associated with Nijmegen breakage syndrome, an autosomal recessive chromosomal instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. The encoded protein is a member of the MRE11/RAD50 double-strand break repair complex which consists of 5 proteins. This gene product is thought to be involved in DNA double-strand break repair and DNA damage-induced checkpoint activation. [provided by RefSeq, Jul 2008]

NBN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 8-89955483-A-G is Benign according to our data. Variant chr8-89955483-A-G is described in ClinVar as [Benign]. Clinvar id is 183701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89955483-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.061 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBN	NM_002485.5 linkuse as main transcript	c.1197T>C	p.Asp399=	synonymous_variant	10/16	ENST00000265433.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBN	ENST00000265433.8 linkuse as main transcript	c.1197T>C	p.Asp399=	synonymous_variant	10/16	1	NM_002485.5	P1

Frequencies

GnomAD3 genomes

AF:

0.509

AC:

77196

AN:

151698

Hom.:

21973

Cov.:

show subpopulations

Gnomad AFR

AF:

0.768

Gnomad AMI

AF:

0.311

Gnomad AMR

AF:

0.522

Gnomad ASJ

AF:

0.347

Gnomad EAS

AF:

0.650

Gnomad SAS

AF:

0.522

Gnomad FIN

AF:

0.433

Gnomad MID

AF:

0.342

Gnomad NFE

AF:

0.361

Gnomad OTH

AF:

0.488

GnomAD3 exomes

AF:

0.465

AC:

116748

AN:

250950

Hom.:

29197

AF XY:

0.453

AC XY:

61478

AN XY:

135692

show subpopulations

Gnomad AFR exome

AF:

0.778

Gnomad AMR exome

AF:

0.577

Gnomad ASJ exome

AF:

0.357

Gnomad EAS exome

AF:

0.648

Gnomad SAS exome

AF:

0.511

Gnomad FIN exome

AF:

0.434

Gnomad NFE exome

AF:

0.363

Gnomad OTH exome

AF:

0.416

GnomAD4 exome

AF:

0.398

AC:

582200

AN:

1461034

Hom.:

123145

Cov.:

AF XY:

0.399

AC XY:

290289

AN XY:

726858

show subpopulations

Gnomad4 AFR exome

AF:

0.785

Gnomad4 AMR exome

AF:

0.574

Gnomad4 ASJ exome

AF:

0.354

Gnomad4 EAS exome

AF:

0.681

Gnomad4 SAS exome

AF:

0.512

Gnomad4 FIN exome

AF:

0.438

Gnomad4 NFE exome

AF:

0.359

Gnomad4 OTH exome

AF:

0.425

GnomAD4 genome

AF:

0.509

AC:

77335

AN:

151816

Hom.:

22042

Cov.:

AF XY:

0.515

AC XY:

38209

AN XY:

74158

show subpopulations

Gnomad4 AFR

AF:

0.768

Gnomad4 AMR

AF:

0.522

Gnomad4 ASJ

AF:

0.347

Gnomad4 EAS

AF:

0.649

Gnomad4 SAS

AF:

0.524

Gnomad4 FIN

AF:

0.433

Gnomad4 NFE

AF:

0.361

Gnomad4 OTH

AF:

0.492

Alfa

AF:

0.397

Hom.:

18261

Bravo

AF:

0.526

Asia WGS

AF:

0.620

AC:

2156

AN:

3478

EpiCase

AF:

0.355

EpiControl

AF:

0.351

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 78% of patients studied by a panel of primary immunodeficiencies. Number of patients: 74. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 16, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Microcephaly, normal intelligence and immunodeficiency

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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.	Sep 16, 2020	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Acute lymphoid leukemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 02, 2014

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. -

Hereditary breast ovarian cancer syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.77

DANN

Benign

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over