rs148205441

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_002485.5(NBN):​c.1405G>T​(p.Asp469Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000373 in 1,608,366 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00024 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

NBN
NM_002485.5 missense

Scores

6
13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:2O:1

Conservation

PhyloP100: 0.391
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.115650475).
BP6
Variant 8-89953684-C-A is Benign according to our data. Variant chr8-89953684-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134873.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=8, Likely_benign=2, not_provided=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NBNNM_002485.5 linkc.1405G>T p.Asp469Tyr missense_variant Exon 11 of 16 ENST00000265433.8 NP_002476.2 O60934

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NBNENST00000265433.8 linkc.1405G>T p.Asp469Tyr missense_variant Exon 11 of 16 1 NM_002485.5 ENSP00000265433.4 O60934

Frequencies

GnomAD3 genomes
AF:
0.000237
AC:
36
AN:
151992
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000821
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000409
AC:
10
AN:
244526
Hom.:
0
AF XY:
0.0000227
AC XY:
3
AN XY:
132420
show subpopulations
Gnomad AFR exome
AF:
0.000573
Gnomad AMR exome
AF:
0.0000293
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000165
AC:
24
AN:
1456374
Hom.:
0
Cov.:
31
AF XY:
0.0000110
AC XY:
8
AN XY:
724560
show subpopulations
Gnomad4 AFR exome
AF:
0.000510
Gnomad4 AMR exome
AF:
0.0000450
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.0000499
GnomAD4 genome
AF:
0.000237
AC:
36
AN:
151992
Hom.:
0
Cov.:
32
AF XY:
0.000269
AC XY:
20
AN XY:
74234
show subpopulations
Gnomad4 AFR
AF:
0.000821
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.000238
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000742
AC:
9

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:10Benign:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabNov 07, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 12, 2025This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 469 of the NBN protein (p.Asp469Tyr). This variant is present in population databases (rs148205441, gnomAD 0.06%). This missense change has been observed in individual(s) with NBN-related cancer (PMID: 35534704, 38446568). This missense change has been observed to be homozygous, hemizygous or homoplasmic in an individual who did not have the expected clinical features for that genetic result (internal data). ClinVar contains an entry for this variant (Variation ID: 134873). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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. -
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoMay 21, 2024The NBN c.1405G>T (p.Asp469Tyr) variant has been reported in the published literature in individuals with pediatric glioma (PMID: 26580448 (2015)), colorectal cancer (PMID: 35534704 (2022)) as well as in reportedly healthy individuals (PMID: 24728327 (2014), 26315354 (2015)). The frequency of this variant in the general population, 0.00066 (16/24412 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxApr 03, 2024In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal and/or family history of breast, thyroid, or other cancers (PMID: 26580448, Lovejoy2018, 35534704); This variant is associated with the following publications: (PMID: 26580448, 24728327, 26315354, 18281469, Lovejoy2018, 35534704) -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJul 14, 2021This 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. -
Uncertain significance, criteria provided, single submittercurationSema4, Sema4Mar 10, 2022- -
not specified Uncertain:1Other:1
not provided, no classification providedreference populationITMISep 19, 2013- -
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 06, 2025Variant summary: NBN c.1405G>T (p.Asp469Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.7e-05 in 252750 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (4.7e-05 vs 0.0025), allowing no conclusion about variant significance. c.1405G>T has been reported in the literature in settings of multigene panel testing among individuals with cancers and in unaffected controls (example, Ramus_2015, Wang_2008, Zhang_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Nijmegen Breakage Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24728327, 26315354, 18281469, 26580448). ClinVar contains an entry for this variant (Variation ID: 134873). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Aplastic anemia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsMar 25, 2024- -
NBN-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesSep 11, 2024The NBN c.1405G>T variant is predicted to result in the amino acid substitution p.Asp469Tyr. This variant has been reported as a germline variant in a pediatric patient with low grade glioma (Zhang et al. 2015. PubMed ID: 26580448 Table S4b) and as a somatic variant in individual(s) with pancreatic cancer (Wang et al. 2008. PubMed ID: 18281469 Table S3 ) but also was reported as a germline variant in healthy controls (Bodian et al. 2014. PubMed ID: 24728327; Ramus et al 2015. PubMed ID: 26315354 Table S4). This variant is reported in 0.066% of alleles in individuals of African descent in gnomAD and is interpreted as a variant of uncertain significance by majority of the submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/134873/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingNational Health Laboratory Service, Universitas Academic Hospital and University of the Free StateApr 19, 2022- -
Hereditary cancer Benign:1
Likely benign, criteria provided, single submitterclinical testingMendelicsFeb 27, 2025This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.26
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.36
T;T
Eigen
Uncertain
0.35
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Benign
0.66
D
LIST_S2
Benign
0.85
D;T
M_CAP
Benign
0.027
D
MetaRNN
Benign
0.12
T;T
MetaSVM
Benign
-0.68
T
MutationAssessor
Uncertain
2.5
M;.
PrimateAI
Benign
0.42
T
PROVEAN
Uncertain
-3.4
D;D
REVEL
Benign
0.15
Sift
Uncertain
0.012
D;D
Sift4G
Benign
0.12
T;T
Polyphen
0.98
D;.
Vest4
0.39
MVP
0.74
MPC
0.089
ClinPred
0.69
D
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.32
gMVP
0.30

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs148205441; hg19: chr8-90965912; API