8-89978341-T-C

Variant names:

Variant summary

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

The NM_002485.5(NBN):c.481-18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000616 in 1,575,712 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000065 ( 2 hom. )

Consequence

NBN
NM_002485.5 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.592

Publications

0 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 8-89978341-T-C is Benign according to our data. Variant chr8-89978341-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 138429. Variant chr8-89978341-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 138429. Variant chr8-89978341-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 138429. Variant chr8-89978341-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 138429. Variant chr8-89978341-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 138429. Variant chr8-89978341-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 138429. Variant chr8-89978341-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 138429. Variant chr8-89978341-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 138429. Variant chr8-89978341-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 138429. Variant chr8-89978341-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 138429. Variant chr8-89978341-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 138429. Variant chr8-89978341-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 138429. Variant chr8-89978341-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 138429. Variant chr8-89978341-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 138429. Variant chr8-89978341-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 138429. Variant chr8-89978341-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 138429. Variant chr8-89978341-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 138429. Variant chr8-89978341-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 138429. Variant chr8-89978341-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 138429. Variant chr8-89978341-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 138429. Variant chr8-89978341-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 138429. Variant chr8-89978341-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 138429. Variant chr8-89978341-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 138429. Variant chr8-89978341-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 138429. Variant chr8-89978341-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 138429.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000646 (92/1423540) while in subpopulation AMR AF = 0.00125 (56/44638). AF 95% confidence interval is 0.000991. There are 2 homozygotes in GnomAdExome4. There are 38 alleles in the male GnomAdExome4 subpopulation. Median coverage is 27. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5 link	c.481-18A>G		intron_variant	Intron 4 of 15	ENST00000265433.8	NP_002476.2	O60934

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8 link	c.481-18A>G		intron_variant	Intron 4 of 15	1	NM_002485.5	ENSP00000265433.4		O60934

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000211

AC:

AN:

250626

AF XY:

0.000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00125

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00164

GnomAD4 exome

AF:

0.0000646

AC:

AN:

1423540

Hom.:

Cov.:

AF XY:

0.0000535

AC XY:

AN XY:

710242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32576

American (AMR)

AF:

0.00125

AC:

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25900

East Asian (EAS)

AF:

0.00

AC:

AN:

39360

South Asian (SAS)

AF:

0.00

AC:

AN:

85292

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.0000269

AC:

AN:

1077622

Other (OTH)

AF:

0.000118

AC:

AN:

59116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41442

American (AMR)

AF:

0.000196

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.0000712

Hom.:

Bravo

AF:

0.000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1

Apr 03, 2015

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.481-18A>G intronic alteration consists of a A to G substitution 18 nucleotides before coding exon 5 in the NBN gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Mar 24, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Microcephaly, normal intelligence and immunodeficiency

Benign:1

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.97

(source)

DANN

Benign

0.77

PhyloP100

-0.59

Mutation Taster

=100/0

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

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over