rs13312981

Positions:

• chr8-89934825-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002485.5(NBN):​c.*757A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0496 in 232,942 control chromosomes in the GnomAD database, including 1,092 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.066 (989 hom., cov: 32)
  • Exomes 𝑓: 0.018 (103 hom.)
• Consequence: NBN NM_002485.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.941

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 8-89934825-T-C is Benign according to our data. Variant chr8-89934825-T-C is described in ClinVar as [Benign]. Clinvar id is 363904.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NBN	NM_002485.5	c.*757A>G		3_prime_UTR_variant	16/16	ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.*757A>G		3_prime_UTR_variant	16/16	1	NM_002485.5	ENSP00000265433	P1

Frequencies

GnomAD3 genomes AF: 0.0658 AC: 10007 AN: 152120 Hom.: 980 Cov.: 32

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0279

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.0115

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00266

Gnomad OTH AF: 0.0570

GnomAD4 exome AF: 0.0185 AC: 1489 AN: 80704 Hom.: 103 Cov.: 0 AF XY: 0.0171 AC XY: 634 AN XY: 37090

Gnomad4 AFR exome AF: 0.229

Gnomad4 AMR exome AF: 0.0272

Gnomad4 ASJ exome AF: 0.0196

Gnomad4 EAS exome AF: 0.00697

Gnomad4 SAS exome AF: 0.0214

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00267

Gnomad4 OTH exome AF: 0.0298

GnomAD4 genome AF: 0.0661 AC: 10056 AN: 152238 Hom.: 989 Cov.: 32 AF XY: 0.0643 AC XY: 4788 AN XY: 74442

Gnomad4 AFR AF: 0.220

Gnomad4 AMR AF: 0.0278

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.0116

Gnomad4 SAS AF: 0.0139

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00266

Gnomad4 OTH AF: 0.0564

Alfa AF: 0.0258 Hom.: 114

Bravo AF: 0.0758

Asia WGS AF: 0.0520 AC: 180 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.8
DANN	Benign	0.70

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: rs13312981; hg19: chr8-90947053;