rs9995

Positions:

• chr8-89933828-A-G

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.*1754T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 232,162 control chromosomes in the GnomAD database, including 12,096 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (7671 hom., cov: 31)
  • Exomes 𝑓: 0.33 (4425 hom.)
• Consequence: NBN NM_002485.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.468

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=-0.95).
• BP6: Variant 8-89933828-A-G is Benign according to our data. Variant chr8-89933828-A-G is described in ClinVar as [Benign]. Clinvar id is 363896.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	Protein	UniProt
NBN	NM_002485.5	c.*1754T>C		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.*1754T>C		3_prime_UTR_variant	16/16	1	NM_002485.5	ENSP00000265433	P1

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48195 AN: 151926 Hom.: 7661 Cov.: 31

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.338

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.305

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.308

GnomAD4 exome AF: 0.332 AC: 26633 AN: 80122 Hom.: 4425 Cov.: 0 AF XY: 0.332 AC XY: 12251 AN XY: 36874

Gnomad4 AFR exome AF: 0.296

Gnomad4 AMR exome AF: 0.301

Gnomad4 ASJ exome AF: 0.272

Gnomad4 EAS exome AF: 0.410

Gnomad4 SAS exome AF: 0.277

Gnomad4 FIN exome AF: 0.397

Gnomad4 NFE exome AF: 0.329

Gnomad4 OTH exome AF: 0.320

GnomAD4 genome AF: 0.317 AC: 48232 AN: 152040 Hom.: 7671 Cov.: 31 AF XY: 0.316 AC XY: 23503 AN XY: 74334

Gnomad4 AFR AF: 0.297

Gnomad4 AMR AF: 0.292

Gnomad4 ASJ AF: 0.261

Gnomad4 EAS AF: 0.406

Gnomad4 SAS AF: 0.320

Gnomad4 FIN AF: 0.305

Gnomad4 NFE AF: 0.333

Gnomad4 OTH AF: 0.306

Alfa AF: 0.321 Hom.: 7700

Bravo AF: 0.312

Asia WGS AF: 0.309 AC: 1075 AN: 3478

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 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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.0
DANN	Benign	0.40

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: rs9995; hg19: chr8-90946056;