dbSNP rs2735383: NBN:c.*541G>C (chr8-89935041-C-G) – ACMG Classification: Benign (-20 pts)

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: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Orphanet, ClinGen
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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002485.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NBN	NM_002485.5	MANE Select	c.*541G>C	3_prime_UTR	Exon 16 of 16	NP_002476.2
NBN	NM_001024688.3		c.*541G>C	3_prime_UTR	Exon 17 of 17	NP_001019859.1	A0A0C4DG07
NBN	NM_001440379.1		c.*541G>C	3_prime_UTR	Exon 16 of 16	NP_001427308.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NBN	ENST00000265433.8	TSL:1 MANE Select	c.*541G>C	3_prime_UTR	Exon 16 of 16	ENSP00000265433.4	O60934
NBN	ENST00000697309.1		c.*407G>C	3_prime_UTR	Exon 15 of 15	ENSP00000513244.1	A0A8V8TKY5
NBN	ENST00000697293.1		c.*541G>C	3_prime_UTR	Exon 17 of 17	ENSP00000513230.1	A0A8V8TM80

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Microcephaly, normal intelligence and immunodeficiency (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over