rs3736640

Positions:

• chr8-89943427-T-A

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.2071-61A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0367 in 1,486,034 control chromosomes in the GnomAD database, including 1,333 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (188 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1145 hom.)
• Consequence: NBN NM_002485.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.777

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=-0.97).
• BP6: Variant 8-89943427-T-A is Benign according to our data. Variant chr8-89943427-T-A is described in ClinVar as [Benign]. Clinvar id is 1226117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0906 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NBN	NM_002485.5	c.2071-61A>T		intron_variant		ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.2071-61A>T		intron_variant		1	NM_002485.5	ENSP00000265433.4

Frequencies

GnomAD3 genomes AF: 0.0416 AC: 6325 AN: 152136 Hom.: 184 Cov.: 32

Gnomad AFR AF: 0.0605

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0507

Gnomad ASJ AF: 0.0372

Gnomad EAS AF: 0.0543

Gnomad SAS AF: 0.0971

Gnomad FIN AF: 0.00980

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0285

Gnomad OTH AF: 0.0492

GnomAD4 exome AF: 0.0361 AC: 48188 AN: 1333780 Hom.: 1145 Cov.: 22 AF XY: 0.0379 AC XY: 25380 AN XY: 669778

Gnomad4 AFR exome AF: 0.0589

Gnomad4 AMR exome AF: 0.0505

Gnomad4 ASJ exome AF: 0.0409

Gnomad4 EAS exome AF: 0.0669

Gnomad4 SAS exome AF: 0.0913

Gnomad4 FIN exome AF: 0.00848

Gnomad4 NFE exome AF: 0.0301

Gnomad4 OTH exome AF: 0.0394

GnomAD4 genome AF: 0.0417 AC: 6346 AN: 152254 Hom.: 188 Cov.: 32 AF XY: 0.0410 AC XY: 3051 AN XY: 74446

Gnomad4 AFR AF: 0.0605

Gnomad4 AMR AF: 0.0508

Gnomad4 ASJ AF: 0.0372

Gnomad4 EAS AF: 0.0540

Gnomad4 SAS AF: 0.0978

Gnomad4 FIN AF: 0.00980

Gnomad4 NFE AF: 0.0285

Gnomad4 OTH AF: 0.0553

Alfa AF: 0.0352 Hom.: 21

Bravo AF: 0.0451

Asia WGS AF: 0.101 AC: 353 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-0.97
CADD	Benign	0.0060
DANN	Benign	0.42

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: rs3736640; hg19: chr8-90955655; COSMIC: COSV55370883;