Genetic Variant NBN:c.703-18G>A (chr8-89970575-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002485.5(NBN):c.703-18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0423 in 1,607,802 control chromosomes in the GnomAD database, including 2,898 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.043 ( 274 hom., cov: 32)

Exomes 𝑓: 0.042 ( 2624 hom. )

Consequence

NBN
NM_002485.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.76

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 8-89970575-C-T is Benign according to our data. Variant chr8-89970575-C-T is described in ClinVar as [Benign]. Clinvar id is 258770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89970575-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5 link	c.703-18G>A		intron_variant	Intron 6 of 15	ENST00000265433.8	NP_002476.2	O60934

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8 link	c.703-18G>A		intron_variant	Intron 6 of 15	1	NM_002485.5	ENSP00000265433.4		O60934

Frequencies

GnomAD3 genomes

AF:

0.0425

AC:

6471

AN:

152138

Hom.:

273

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00997

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.110

Gnomad ASJ

AF:

0.0159

Gnomad EAS

AF:

0.187

Gnomad SAS

AF:

0.0732

Gnomad FIN

AF:

0.0778

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0304

Gnomad OTH

AF:

0.0412

GnomAD3 exomes

AF:

0.0716

AC:

17795

AN:

248624

Hom.:

1243

AF XY:

0.0663

AC XY:

8946

AN XY:

134956

show subpopulations

Gnomad AFR exome

AF:

0.00914

Gnomad AMR exome

AF:

0.196

Gnomad ASJ exome

AF:

0.0201

Gnomad EAS exome

AF:

0.182

Gnomad SAS exome

AF:

0.0686

Gnomad FIN exome

AF:

0.0762

Gnomad NFE exome

AF:

0.0292

Gnomad OTH exome

AF:

0.0573

GnomAD4 exome

AF:

0.0422

AC:

61470

AN:

1455546

Hom.:

2624

Cov.:

AF XY:

0.0425

AC XY:

30768

AN XY:

724406

show subpopulations

Gnomad4 AFR exome

AF:

0.00807

Gnomad4 AMR exome

AF:

0.185

Gnomad4 ASJ exome

AF:

0.0196

Gnomad4 EAS exome

AF:

0.193

Gnomad4 SAS exome

AF:

0.0686

Gnomad4 FIN exome

AF:

0.0725

Gnomad4 NFE exome

AF:

0.0292

Gnomad4 OTH exome

AF:

0.0429

GnomAD4 genome

AF:

0.0425

AC:

6478

AN:

152256

Hom.:

274

Cov.:

AF XY:

0.0477

AC XY:

3551

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00991

Gnomad4 AMR

AF:

0.110

Gnomad4 ASJ

AF:

0.0159

Gnomad4 EAS

AF:

0.188

Gnomad4 SAS

AF:

0.0737

Gnomad4 FIN

AF:

0.0778

Gnomad4 NFE

AF:

0.0304

Gnomad4 OTH

AF:

0.0412

Alfa

AF:

0.0332

Hom.:

Bravo

AF:

0.0465

Asia WGS

AF:

0.136

AC:

472

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2017

Counsyl

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 06, 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

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 21. Only high quality variants are reported. -

Acute lymphoid leukemia

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome

Benign:1

Apr 19, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.81

DANN

Benign

0.51

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