rs1063053

Positions:

• chr8-89935309-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.*273G>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 0.314 in 381,352 control chromosomes in the GnomAD database, including 19,295 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7150 hom., cov: 32)
  • Exomes 𝑓: 0.32 (12145 hom.)
• Consequence: NBN NM_002485.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.123

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 8-89935309-C-T is Benign according to our data. Variant chr8-89935309-C-T is described in ClinVar as [Benign]. Clinvar id is 363909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.391 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBN	NM_002485.5	c.*273G>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.*273G>A		3_prime_UTR_variant	16/16	1	NM_002485.5	P1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46343 AN: 151726 Hom.: 7143 Cov.: 32

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.288

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.406

Gnomad SAS AF: 0.319

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.300

GnomAD4 exome AF: 0.319 AC: 73323 AN: 229508 Hom.: 12145 Cov.: 3 AF XY: 0.318 AC XY: 37880 AN XY: 119076

Gnomad4 AFR exome AF: 0.252

Gnomad4 AMR exome AF: 0.290

Gnomad4 ASJ exome AF: 0.263

Gnomad4 EAS exome AF: 0.408

Gnomad4 SAS exome AF: 0.289

Gnomad4 FIN exome AF: 0.307

Gnomad4 NFE exome AF: 0.324

Gnomad4 OTH exome AF: 0.312

GnomAD4 genome AF: 0.305 AC: 46376 AN: 151844 Hom.: 7150 Cov.: 32 AF XY: 0.305 AC XY: 22615 AN XY: 74190

Gnomad4 AFR AF: 0.258

Gnomad4 AMR AF: 0.288

Gnomad4 ASJ AF: 0.261

Gnomad4 EAS AF: 0.405

Gnomad4 SAS AF: 0.321

Gnomad4 FIN AF: 0.306

Gnomad4 NFE AF: 0.332

Gnomad4 OTH AF: 0.297

Alfa AF: 0.320 Hom.: 13277

Bravo AF: 0.298

Asia WGS AF: 0.306 AC: 1063 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 24, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.4
DANN	Benign	0.62

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: rs1063053; hg19: chr8-90947537;