Genetic Variant NM_002485.5:c.283G>A (chr8-89981412-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_002485.5(NBN):c.283G>A(p.Asp95Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00226 in 1,614,012 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D95H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 4 hom. )

Consequence

NBN
NM_002485.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:20O:1

Conservation

PhyloP100: 4.11

Publications

34 publications found

Variant links:

COSMIC-nc: COSV104545419

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02321592).

BP6

Variant 8-89981412-C-T is Benign according to our data. Variant chr8-89981412-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127869.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00183 (279/152300) while in subpopulation NFE AF = 0.0031 (211/68022). AF 95% confidence interval is 0.00276. There are 0 homozygotes in GnomAd4. There are 116 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AR,AD gene

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	HGVSp	Effect	Exon Rank	Protein	UniProt
NBN	NM_002485.5	MANE Select	c.283G>A	p.Asp95Asn	missense	Exon 3 of 16	NP_002476.2
NBN	NM_001024688.3		c.37G>A	p.Asp13Asn	missense	Exon 4 of 17	NP_001019859.1	A0A0C4DG07
NBN	NM_001440379.1		c.37G>A	p.Asp13Asn	missense	Exon 3 of 16	NP_001427308.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NBN	ENST00000265433.8	TSL:1 MANE Select	c.283G>A	p.Asp95Asn	missense	Exon 3 of 16	ENSP00000265433.4	O60934
NBN	ENST00000697309.1		c.283G>A	p.Asp95Asn	missense	Exon 3 of 15	ENSP00000513244.1	A0A8V8TKY5
NBN	ENST00000697293.1		c.283G>A	p.Asp95Asn	missense	Exon 3 of 17	ENSP00000513230.1	A0A8V8TM80

Frequencies

GnomAD3 genomes

AF:

0.00183

AC:

279

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000627

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00310

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00173

AC:

435

AN:

251380

AF XY:

0.00172

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.000607

Gnomad ASJ exome

AF:

0.00407

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00295

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00231

AC:

3373

AN:

1461712

Hom.:

Cov.:

AF XY:

0.00224

AC XY:

1627

AN XY:

727148

show subpopulations

African (AFR)

AF:

0.000388

AC:

AN:

33472

American (AMR)

AF:

0.000738

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00429

AC:

112

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.000359

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.000375

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.000695

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00275

AC:

3054

AN:

1111916

Other (OTH)

AF:

0.00176

AC:

106

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

170

339

509

678

848

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

228

342

456

570

<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:

0.00183

AC:

279

AN:

152300

Hom.:

Cov.:

AF XY:

0.00156

AC XY:

116

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000626

AC:

AN:

41562

American (AMR)

AF:

0.000588

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00310

AC:

211

AN:

68022

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00288

Hom.:

Bravo

AF:

0.00182

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00186

AC:

226

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00333

EpiControl

AF:

0.00308

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (8)

Microcephaly, normal intelligence and immunodeficiency (6)

not specified (6)

Hereditary cancer-predisposing syndrome (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.59

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.093

MetaRNN

Benign

0.023

MetaSVM

Uncertain

0.49

MutationAssessor

Pathogenic

3.3

PhyloP100

4.1

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-4.3

REVEL

Uncertain

0.58

Sift

Uncertain

0.012

Sift4G

Uncertain

0.040

Polyphen

1.0

Vest4

0.59

MVP

0.87

MPC

0.40

ClinPred

0.063

GERP RS

4.8

PromoterAI

-0.017

Neutral

(source)

Varity_R

0.61

gMVP

0.70

Mutation Taster

=99/1

polymorphism

(source)

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

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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