chr8-89953684-C-A
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
Consequence
NM_002485.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000237 AC: 36AN: 151992Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000409 AC: 10AN: 244526Hom.: 0 AF XY: 0.0000227 AC XY: 3AN XY: 132420
GnomAD4 exome AF: 0.0000165 AC: 24AN: 1456374Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 724560
GnomAD4 genome AF: 0.000237 AC: 36AN: 151992Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20AN XY: 74234
ClinVar
Submissions by phenotype
Microcephaly, normal intelligence and immunodeficiency Uncertain:3
This 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. -
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not provided Uncertain:2
In 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) -
The 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. -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
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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. -
not specified Uncertain:1Other:1
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Variant 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
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NBN-related disorder Uncertain:1
The 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
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Hereditary cancer Benign:1
This 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at