8-89933370-C-T

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.*2212G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0371 in 219,934 control chromosomes in the GnomAD database, including 424 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.033 (224 hom., cov: 32)
  • Exomes 𝑓: 0.046 (200 hom.)
• Consequence: NBN NM_002485.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.410

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=-0.95).
• BP6: Variant 8-89933370-C-T is Benign according to our data. Variant chr8-89933370-C-T is described in ClinVar as [Benign]. Clinvar id is 363891.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBN	NM_002485.5	c.*2212G>A		3_prime_UTR_variant	16/16	ENST00000265433.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBN	ENST00000265433.8	c.*2212G>A		3_prime_UTR_variant	16/16	1	NM_002485.5	P1

Frequencies

GnomAD3 genomes AF: 0.0332 AC: 5042 AN: 152094 Hom.: 222 Cov.: 32

Gnomad AFR AF: 0.00517

Gnomad AMI AF: 0.0363

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.171

Gnomad SAS AF: 0.0713

Gnomad FIN AF: 0.0475

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0186

Gnomad OTH AF: 0.0378

GnomAD4 exome AF: 0.0459 AC: 3106 AN: 67722 Hom.: 200 Cov.: 0 AF XY: 0.0457 AC XY: 1435 AN XY: 31398

Gnomad4 AFR exome AF: 0.00546

Gnomad4 AMR exome AF: 0.118

Gnomad4 ASJ exome AF: 0.00717

Gnomad4 EAS exome AF: 0.192

Gnomad4 SAS exome AF: 0.0870

Gnomad4 FIN exome AF: 0.0227

Gnomad4 NFE exome AF: 0.0170

Gnomad4 OTH exome AF: 0.0335

GnomAD4 genome AF: 0.0332 AC: 5050 AN: 152212 Hom.: 224 Cov.: 32 AF XY: 0.0369 AC XY: 2742 AN XY: 74402

Gnomad4 AFR AF: 0.00515

Gnomad4 AMR AF: 0.111

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.171

Gnomad4 SAS AF: 0.0713

Gnomad4 FIN AF: 0.0475

Gnomad4 NFE AF: 0.0186

Gnomad4 OTH AF: 0.0388

Alfa AF: 0.0232 Hom.: 122

Bravo AF: 0.0387

Asia WGS AF: 0.126 AC: 436 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 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	-0.95
Cadd	Benign	0.89
Dann	Benign	0.26

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: rs10464867; hg19: chr8-90945598;