rs13312986

Positions:

• chr8-89933890-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.*1692A>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 0.0378 in 232,162 control chromosomes in the GnomAD database, including 456 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.033 (226 hom., cov: 32)
  • Exomes 𝑓: 0.046 (230 hom.)
• Consequence: NBN NM_002485.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.29

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=-0.93).
• BP6: Variant 8-89933890-T-C is Benign according to our data. Variant chr8-89933890-T-C is described in ClinVar as [Benign]. Clinvar id is 363897.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBN	NM_002485.5	c.*1692A>G		3_prime_UTR_variant	16/16	ENST00000265433.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBN	ENST00000265433.8	c.*1692A>G		3_prime_UTR_variant	16/16	1	NM_002485.5	P1

Frequencies

GnomAD3 genomes AF: 0.0332 AC: 5054 AN: 152082 Hom.: 224 Cov.: 32

Gnomad AFR AF: 0.00517

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.0716

Gnomad FIN AF: 0.0476

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0187

Gnomad OTH AF: 0.0373

GnomAD4 exome AF: 0.0465 AC: 3718 AN: 79960 Hom.: 230 Cov.: 0 AF XY: 0.0461 AC XY: 1696 AN XY: 36752

Gnomad4 AFR exome AF: 0.00545

Gnomad4 AMR exome AF: 0.123

Gnomad4 ASJ exome AF: 0.00730

Gnomad4 EAS exome AF: 0.195

Gnomad4 SAS exome AF: 0.0939

Gnomad4 FIN exome AF: 0.0172

Gnomad4 NFE exome AF: 0.0179

Gnomad4 OTH exome AF: 0.0345

GnomAD4 genome AF: 0.0333 AC: 5062 AN: 152202 Hom.: 226 Cov.: 32 AF XY: 0.0369 AC XY: 2749 AN XY: 74406

Gnomad4 AFR AF: 0.00515

Gnomad4 AMR AF: 0.111

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.172

Gnomad4 SAS AF: 0.0717

Gnomad4 FIN AF: 0.0476

Gnomad4 NFE AF: 0.0187

Gnomad4 OTH AF: 0.0383

Alfa AF: 0.0242 Hom.: 200

Bravo AF: 0.0387

Asia WGS AF: 0.126 AC: 435 AN: 3472

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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.5
DANN	Benign	0.70

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: rs13312986; hg19: chr8-90946118;