rs201373377

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_002485.5(NBN):c.1204A>G(p.Thr402Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T402T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

NBN
NM_002485.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0110

Publications

2 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0405851).

BP6

Variant 8-89955476-T-C is Benign according to our data. Variant chr8-89955476-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187410. Variant chr8-89955476-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187410. Variant chr8-89955476-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187410. Variant chr8-89955476-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187410. Variant chr8-89955476-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187410. Variant chr8-89955476-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187410. Variant chr8-89955476-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187410. Variant chr8-89955476-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187410. Variant chr8-89955476-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187410. Variant chr8-89955476-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187410. Variant chr8-89955476-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187410. Variant chr8-89955476-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187410. Variant chr8-89955476-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187410. Variant chr8-89955476-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187410. Variant chr8-89955476-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187410. Variant chr8-89955476-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187410. Variant chr8-89955476-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187410. Variant chr8-89955476-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187410. Variant chr8-89955476-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187410. Variant chr8-89955476-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187410. Variant chr8-89955476-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187410. Variant chr8-89955476-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187410. Variant chr8-89955476-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 187410.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5 link	c.1204A>G	p.Thr402Ala	missense_variant	Exon 10 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.1204A>G	p.Thr402Ala	missense_variant	Exon 10 of 16	1	NM_002485.5	ENSP00000265433.4		O60934

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251074

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461436

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727020

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.000202

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111674

Other (OTH)

AF:

0.00

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41542

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67984

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.725

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency

Uncertain:2

May 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 402 of the NBN protein (p.Thr402Ala). This variant is present in population databases (rs201373377, gnomAD 0.02%). This missense change has been observed in individual(s) with NBN-related cancer (PMID: 36346689). ClinVar contains an entry for this variant (Variation ID: 187410). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Nov 07, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Oct 26, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.58

CADD

Benign

3.7

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.36

T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.041

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;.

PhyloP100

-0.011

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.0060

Sift

Benign

0.22

T;T

Sift4G

Benign

0.38

T;T

Polyphen

0.0030

B;.

Vest4

0.087

MVP

0.65

MPC

0.067

ClinPred

0.0090

GERP RS

-1.4

Varity_R

0.024

gMVP

0.16

Mutation Taster

=93/7

polymorphism

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over