rs14448

Variant names:

• chr8-89933605-A-G
• rs14448
• NM_002485.5:c.*1977T>C

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.*1977T>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 0.165 in 232,030 control chromosomes in the GnomAD database, including 6,217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (5114 hom., cov: 32)
  • Exomes 𝑓: 0.12 (1103 hom.)
• Consequence: NBN NM_002485.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.44

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=-0.96).
• BP6: Variant 8-89933605-A-G is Benign according to our data. Variant chr8-89933605-A-G is described in ClinVar as [Benign]. Clinvar id is 363892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.45 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5	c.*1977T>C		3_prime_UTR_variant	Exon 16 of 16	ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433	c.*1977T>C		3_prime_UTR_variant	Exon 16 of 16	1	NM_002485.5	ENSP00000265433.4

Frequencies

GnomAD3 genomes AF: 0.190 AC: 28888 AN: 152046 Hom.: 5086 Cov.: 32

Gnomad AFR AF: 0.455

Gnomad AMI AF: 0.0462

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.0648

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.0564

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0513

Gnomad OTH AF: 0.178

GnomAD4 exome AF: 0.116 AC: 9295 AN: 79866 Hom.: 1103 Cov.: 0 AF XY: 0.113 AC XY: 4155 AN XY: 36738

Gnomad4 AFR exome AF: 0.462

Gnomad4 AMR exome AF: 0.219

Gnomad4 ASJ exome AF: 0.0711

Gnomad4 EAS exome AF: 0.282

Gnomad4 SAS exome AF: 0.214

Gnomad4 FIN exome AF: 0.0172

Gnomad4 NFE exome AF: 0.0498

Gnomad4 OTH exome AF: 0.124

GnomAD4 genome AF: 0.190 AC: 28981 AN: 152164 Hom.: 5114 Cov.: 32 AF XY: 0.190 AC XY: 14156 AN XY: 74396

Gnomad4 AFR AF: 0.456

Gnomad4 AMR AF: 0.208

Gnomad4 ASJ AF: 0.0648

Gnomad4 EAS AF: 0.239

Gnomad4 SAS AF: 0.190

Gnomad4 FIN AF: 0.0564

Gnomad4 NFE AF: 0.0513

Gnomad4 OTH AF: 0.185

Alfa AF: 0.0905 Hom.: 1428

Bravo AF: 0.215

Asia WGS AF: 0.295 AC: 1026 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.53
DANN	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs14448; hg19: chr8-90945833; COSMIC: COSV55375146; COSMIC: COSV55375146;