Genetic Variant NBN:p.Asp399Asp (chr8-89955483-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002485.5(NBN):c.1197T>C(p.Asp399Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 1,612,850 control chromosomes in the GnomAD database, including 145,187 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.51 ( 22042 hom., cov: 31)

Exomes 𝑓: 0.40 ( 123145 hom. )

Consequence

NBN
NM_002485.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: -0.0610

Publications

75 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 8-89955483-A-G is Benign according to our data. Variant chr8-89955483-A-G is described in ClinVar as Benign. ClinVar VariationId is 183701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.061 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.761 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	HGVSp	Effect	Exon Rank	Protein	UniProt
NBN	NM_002485.5	MANE Select	c.1197T>C	p.Asp399Asp	synonymous	Exon 10 of 16	NP_002476.2
NBN	NM_001024688.3		c.951T>C	p.Asp317Asp	synonymous	Exon 11 of 17	NP_001019859.1	A0A0C4DG07
NBN	NM_001440379.1		c.951T>C	p.Asp317Asp	synonymous	Exon 10 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.1197T>C	p.Asp399Asp	synonymous	Exon 10 of 16	ENSP00000265433.4	O60934
NBN	ENST00000697309.1		c.1197T>C	p.Asp399Asp	synonymous	Exon 10 of 15	ENSP00000513244.1	A0A8V8TKY5
NBN	ENST00000697293.1		c.1197T>C	p.Asp399Asp	synonymous	Exon 10 of 17	ENSP00000513230.1	A0A8V8TM80

Frequencies

GnomAD3 genomes

AF:

0.509

AC:

77196

AN:

151698

Hom.:

21973

Cov.:

show subpopulations

Gnomad AFR

AF:

0.768

Gnomad AMI

AF:

0.311

Gnomad AMR

AF:

0.522

Gnomad ASJ

AF:

0.347

Gnomad EAS

AF:

0.650

Gnomad SAS

AF:

0.522

Gnomad FIN

AF:

0.433

Gnomad MID

AF:

0.342

Gnomad NFE

AF:

0.361

Gnomad OTH

AF:

0.488

GnomAD2 exomes

AF:

0.465

AC:

116748

AN:

250950

AF XY:

0.453

show subpopulations

Gnomad AFR exome

AF:

0.778

Gnomad AMR exome

AF:

0.577

Gnomad ASJ exome

AF:

0.357

Gnomad EAS exome

AF:

0.648

Gnomad FIN exome

AF:

0.434

Gnomad NFE exome

AF:

0.363

Gnomad OTH exome

AF:

0.416

GnomAD4 exome

AF:

0.398

AC:

582200

AN:

1461034

Hom.:

123145

Cov.:

AF XY:

0.399

AC XY:

290289

AN XY:

726858

show subpopulations

African (AFR)

AF:

0.785

AC:

26263

AN:

33452

American (AMR)

AF:

0.574

AC:

25666

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.354

AC:

9239

AN:

26118

East Asian (EAS)

AF:

0.681

AC:

27035

AN:

39674

South Asian (SAS)

AF:

0.512

AC:

44162

AN:

86230

European-Finnish (FIN)

AF:

0.438

AC:

23344

AN:

53354

Middle Eastern (MID)

AF:

0.392

AC:

2256

AN:

5762

European-Non Finnish (NFE)

AF:

0.359

AC:

398603

AN:

1111388

Other (OTH)

AF:

0.425

AC:

25632

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

17861

35722

53582

71443

89304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13000

26000

39000

52000

65000

<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:

0.509

AC:

77335

AN:

151816

Hom.:

22042

Cov.:

AF XY:

0.515

AC XY:

38209

AN XY:

74158

show subpopulations

African (AFR)

AF:

0.768

AC:

31818

AN:

41412

American (AMR)

AF:

0.522

AC:

7965

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.347

AC:

1205

AN:

3470

East Asian (EAS)

AF:

0.649

AC:

3347

AN:

5160

South Asian (SAS)

AF:

0.524

AC:

2522

AN:

4814

European-Finnish (FIN)

AF:

0.433

AC:

4545

AN:

10496

Middle Eastern (MID)

AF:

0.350

AC:

103

AN:

294

European-Non Finnish (NFE)

AF:

0.361

AC:

24508

AN:

67894

Other (OTH)

AF:

0.492

AC:

1038

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1715

3431

5146

6862

8577

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

658

1316

1974

2632

3290

<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:

0.411

Hom.:

29149

Bravo

AF:

0.526

Asia WGS

AF:

0.620

AC:

2156

AN:

3478

EpiCase

AF:

0.355

EpiControl

AF:

0.351

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Microcephaly, normal intelligence and immunodeficiency (5)

not provided (3)

Hereditary cancer-predisposing syndrome (2)

Acute lymphoid leukemia (1)

Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.77

(source)

DANN

Benign

0.27

PhyloP100

-0.061

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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