rs2735383

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002485.5(NBN):c.*541G>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 0.319 in 233,322 control chromosomes in the GnomAD database, including 11,921 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 7464 hom., cov: 32)

Exomes 𝑓: 0.33 ( 4457 hom. )

Consequence

NBN
NM_002485.5 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.07

Publications

61 publications found

Variant links:

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

NBN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 8-89935041-C-G is Benign according to our data. Variant chr8-89935041-C-G is described in ClinVar as Benign. ClinVar VariationId is 363905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5 link	c.*541G>C		3_prime_UTR_variant	Exon 16 of 16	ENST00000265433.8	NP_002476.2	O60934

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8 link	c.*541G>C		3_prime_UTR_variant	Exon 16 of 16	1	NM_002485.5	ENSP00000265433.4		O60934

Frequencies

GnomAD3 genomes

AF:

0.313

AC:

47533

AN:

151868

Hom.:

7454

Cov.:

show subpopulations

Gnomad AFR

AF:

0.282

Gnomad AMI

AF:

0.338

Gnomad AMR

AF:

0.290

Gnomad ASJ

AF:

0.261

Gnomad EAS

AF:

0.407

Gnomad SAS

AF:

0.318

Gnomad FIN

AF:

0.306

Gnomad MID

AF:

0.266

Gnomad NFE

AF:

0.333

Gnomad OTH

AF:

0.305

GnomAD4 exome

AF:

0.330

AC:

26838

AN:

81336

Hom.:

4457

Cov.:

AF XY:

0.330

AC XY:

12426

AN XY:

37626

show subpopulations

African (AFR)

AF:

0.276

AC:

1068

AN:

3870

American (AMR)

AF:

0.300

AC:

770

AN:

2566

Ashkenazi Jewish (ASJ)

AF:

0.271

AC:

1374

AN:

5066

East Asian (EAS)

AF:

0.407

AC:

4553

AN:

11194

South Asian (SAS)

AF:

0.285

AC:

224

AN:

786

European-Finnish (FIN)

AF:

0.368

AC:

AN:

Middle Eastern (MID)

AF:

0.264

AC:

130

AN:

492

European-Non Finnish (NFE)

AF:

0.328

AC:

16573

AN:

50566

Other (OTH)

AF:

0.315

AC:

2121

AN:

6728

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

788

1577

2365

3154

3942

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

264

352

440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.313

AC:

47571

AN:

151986

Hom.:

7464

Cov.:

AF XY:

0.312

AC XY:

23181

AN XY:

74260

show subpopulations

African (AFR)

AF:

0.282

AC:

11682

AN:

41454

American (AMR)

AF:

0.291

AC:

4444

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.261

AC:

905

AN:

3470

East Asian (EAS)

AF:

0.406

AC:

2105

AN:

5182

South Asian (SAS)

AF:

0.320

AC:

1541

AN:

4814

European-Finnish (FIN)

AF:

0.306

AC:

3219

AN:

10506

Middle Eastern (MID)

AF:

0.279

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.333

AC:

22648

AN:

67954

Other (OTH)

AF:

0.303

AC:

637

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1698

3395

5093

6790

8488

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

480

960

1440

1920

2400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.329

Hom.:

1108

Bravo

AF:

0.306

Asia WGS

AF:

0.307

AC:

1071

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency

Benign:2

Mar 06, 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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

-0.83

CADD

Benign

8.5

(source)

DANN

Benign

0.74

PhyloP100

-1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

0.97

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over