NM_002485.5:c.*1209A>C

Variant names:

• chr8-89934373-T-G
• rs1063054
• NM_002485.5:c.*1209A>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.*1209A>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 0.323 in 232,660 control chromosomes in the GnomAD database, including 12,135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (7680 hom., cov: 32)
  • Exomes 𝑓: 0.33 (4455 hom.)
• Consequence: NBN NM_002485.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.108

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=-0.9).
• BP6: Variant 8-89934373-T-G is Benign according to our data. Variant chr8-89934373-T-G is described in ClinVar as [Benign]. Clinvar id is 363898.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 rank	MANE	Protein	UniProt
NBN	NM_002485.5	c.*1209A>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.*1209A>C		3_prime_UTR_variant	Exon 16 of 16	1	NM_002485.5	ENSP00000265433.4

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48227 AN: 151928 Hom.: 7670 Cov.: 32

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.335

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.406

Gnomad SAS AF: 0.320

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.308

GnomAD4 exome AF: 0.332 AC: 26803 AN: 80614 Hom.: 4455 Cov.: 0 AF XY: 0.332 AC XY: 12309 AN XY: 37044

Gnomad4 AFR exome AF: 0.295

Gnomad4 AMR exome AF: 0.301

Gnomad4 ASJ exome AF: 0.272

Gnomad4 EAS exome AF: 0.409

Gnomad4 SAS exome AF: 0.284

Gnomad4 FIN exome AF: 0.393

Gnomad4 NFE exome AF: 0.329

Gnomad4 OTH exome AF: 0.320

GnomAD4 genome AF: 0.317 AC: 48265 AN: 152046 Hom.: 7680 Cov.: 32 AF XY: 0.316 AC XY: 23521 AN XY: 74318

Gnomad4 AFR AF: 0.297

Gnomad4 AMR AF: 0.293

Gnomad4 ASJ AF: 0.261

Gnomad4 EAS AF: 0.406

Gnomad4 SAS AF: 0.322

Gnomad4 FIN AF: 0.306

Gnomad4 NFE AF: 0.333

Gnomad4 OTH AF: 0.306

Alfa AF: 0.328 Hom.: 1679

Bravo AF: 0.312

Asia WGS AF: 0.310 AC: 1079 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

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	-0.90
CADD	Benign	1.6
DANN	Benign	0.71

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: rs1063054; hg19: chr8-90946601;