rs769418

Positions:

• chr8-89970575-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.76

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 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
NBN	NM_002485.5	c.703-18G>A		intron_variant		ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.703-18G>A		intron_variant		1	NM_002485.5	ENSP00000265433.4

Frequencies

GnomAD3 genomes AF: 0.0425 AC: 6471 AN: 152138 Hom.: 273 Cov.: 32

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

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.: 31 AF XY: 0.0425 AC XY: 30768 AN XY: 724406

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.: 32 AF XY: 0.0477 AC XY: 3551 AN XY: 74442

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.: 27

Bravo AF: 0.0465

Asia WGS AF: 0.136 AC: 472 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 14, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 21. Only high quality variants are reported. -

Microcephaly, normal intelligence and immunodeficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Counsyl	Sep 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Acute lymphoid leukemia Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

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	-0.85
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

Other links and lift over

dbSNP: rs769418; hg19: chr8-90982803; COSMIC: COSV55371926;