rs1063054

Variant names:

• chr8-89934373-T-G
• rs1063054
• NM_002485.5:c.*1209A>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 32 publications found

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]

NBN Gene-Disease associations (from GenCC):

• Nijmegen breakage syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• idiopathic aplastic anemia

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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	ENST00000265433.8	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

African (AFR) AF: 0.295 AC: 1146 AN: 3880

American (AMR) AF: 0.301 AC: 748 AN: 2484

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 1387 AN: 5102

East Asian (EAS) AF: 0.409 AC: 4650 AN: 11362

South Asian (SAS) AF: 0.284 AC: 198 AN: 696

European-Finnish (FIN) AF: 0.393 AC: 22 AN: 56

Middle Eastern (MID) AF: 0.267 AC: 131 AN: 490

European-Non Finnish (NFE) AF: 0.329 AC: 16361 AN: 49794

Other (OTH) AF: 0.320 AC: 2160 AN: 6750

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

African (AFR) AF: 0.297 AC: 12319 AN: 41454

American (AMR) AF: 0.293 AC: 4478 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 905 AN: 3472

East Asian (EAS) AF: 0.406 AC: 2097 AN: 5170

South Asian (SAS) AF: 0.322 AC: 1550 AN: 4816

European-Finnish (FIN) AF: 0.306 AC: 3238 AN: 10572

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.333 AC: 22646 AN: 67970

Other (OTH) AF: 0.306 AC: 646 AN: 2112

Alfa AF: 0.328 Hom.: 2869

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
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1063054; hg19: chr8-90946601;