rs200287925
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3_StrongPP5
The NM_001024688.3(NBN):c.-170C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,613,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001024688.3 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NBN | NM_002485.5 | c.127C>T | p.Arg43* | stop_gained | 2/16 | ENST00000265433.8 | NP_002476.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NBN | ENST00000265433.8 | c.127C>T | p.Arg43* | stop_gained | 2/16 | 1 | NM_002485.5 | ENSP00000265433.4 |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152078Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251426Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135882
GnomAD4 exome AF: 0.0000397 AC: 58AN: 1461658Hom.: 0 Cov.: 30 AF XY: 0.0000330 AC XY: 24AN XY: 727138
GnomAD4 genome AF: 0.0000592 AC: 9AN: 152078Hom.: 0 Cov.: 33 AF XY: 0.0000808 AC XY: 6AN XY: 74286
ClinVar
Submissions by phenotype
Microcephaly, normal intelligence and immunodeficiency Pathogenic:8
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 14, 2024 | This sequence change creates a premature translational stop signal (p.Arg43*) in the NBN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NBN are known to be pathogenic (PMID: 9590180, 16415040). This variant is present in population databases (rs200287925, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with triple negative breast cancer (PMID: 24763289, 26976419). ClinVar contains an entry for this variant (Variation ID: 142203). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 21, 2020 | A heterozygous nonsense variant was identified, NM_002485.4(NBN):c.127C>T in exon 2 of 16 of the NBN gene. (NB: This variant is non-coding in an alternative transcript). This nonsense variant is predicted to create a change of an arginine to a stop at amino acid position 43 of the protein; NP_002476.2(NBN):p.(Arg43*), resulting in the loss of normal protein function through nonsense-mediated decay (NMD). The variant is present in the gnomAD population database at a global population frequency of 0.003% (8 heterozygotes; 0 homozygotes) with a European (Finnish) sub-population frequency of 0.02%. The variant has been previously reported in patients with breast cancer (ClinVar, Tessitore, A. et al. (2003), LaDuca, H. et al. (2014), Young, E. et al. (2016), Thompson, E. et al. (2016), Tung, N. et al. (2016)). Other variants predicted to cause NMD have also been reported as pathogenic (ClinVar). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 04, 2022 | Variant summary: NBN c.127C>T (p.Arg43X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.2e-05 in 251426 control chromosomes (gnomAD). c.127C>T has been reported in the literature in individuals affected with various cancers, including those of the breast and brain (e.g. Damiola_2014, LaDuca_2014, Lu_2015, Thompson_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, six as likely pathogenic, and four as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 18, 2018 | The p.Arg43X variant in NBN has been not been reported in individuals with Nijme gen breakage syndrome. However, it has reported in 1 individual with hereditary cancer and two individuals with breast cancer (LaDuca 2014, Tung 2016, Thompson 2016) and has been reported in ClinVar (Variation ID: 142203). The variant has b een identified in 4/22288 Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs200287925). Although this v ariant has been seen in the general population, its frequency is low enough to b e consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 43 which is predicted to lead to a tru ncated or absent protein. Loss of function of the NBS gene is an established dis ease mechanism in Nijmegen breakage syndrome. In summary, although additional st udies are required to fully establish its clinical significance, the p.Arg43X va riant is likely pathogenic for Nijmegen breakage syndrome. in an autosomal reces sive manner based upon predicted impact to the protein and absence from controls ,. ACMG/AMP Criteria applied: PVS1; PM2. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 31, 2021 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 05, 2016 | - - |
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 22, 2024 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal history of breast cancer or glioblastoma (PMID: 24894818, 26786923, 26976419, 32318955, 26689913); This variant is associated with the following publications: (PMID: 24763289, 29922827, 29625052, 25032700, 26976419, 26786923, 19523210, 24894818, 26787654, 29555771, 26689913, 32318955, 31980526, 34072463, 32427313, 33804961, 35257886, 12433983, 11279524, 12708449, 19105185, 36988593, 33344249, 34887416, 34308104, 36451132) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 03, 2019 | DNA sequence analysis of the NBN gene demonstrated a sequence change, c.127C>T, which results in the creation of a premature stop codon at amino acid position 43, p.Arg43*. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated NBN protein with potentially abnormal function. This sequence change has been described in the gnomAD database with a population frequency of 0.018% in Finnish subpopulation (dbSNP rs200287925). This sequence change has previously been described in a patient with triple-negative breast cancer and a family history of lung cancer, exocrine pancreatic cancer and CNS tumor (PMID: 26976419). Additionally it has also been identified in two patients with personal and/or family history of breast cancer but limited clinical information was provided (PMID: 26786923, PMID: 29555771). Truncating variants in the NBN gene are known to be pathogenic. These collective evidences indicate that this sequence change is likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 13, 2023 | The p.R43* variant (also known as c.127C>T), located in coding exon 2 of the NBN gene, results from a C to T substitution at nucleotide position 127. This changes the amino acid from an arginine to a stop codon within coding exon 2. The predicted stop codon occurs within the first 150 nucleotides of theNBN gene. This alteration may escape nonsense-mediated mRNAdecay and/or be rescued by re-initiation (Rivas MA et al. Science. 2015 May 8;348(6235):666-9; Lindeboom RGH et al. Nat. Genet. 2016 Oct;48(10):1112-8; Rhee JK et al. Sci. Rep. 2017 May 10;7(1):1653). Re-initiation on a downstream methionine would disrupt the forkhead-associated domain (FHA) which has been implicated in NBN function (Zhao S et al. Nucleic Acids Res. 2002 Nov;30:4815-22). However, the exact functional impact of this particular alteration is unknown at this time. This alteration has been reported in patients with breast cancer (Damiola F et al. Breast Cancer Res. 2014 Jun;16:R58; Thompson ER et al. J. Clin. Oncol. 2016 May;34:1455-9; Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8). It has also been identified in trans with a possible deleterious variant in an individual without features of Nijmegen breakage syndrome (Ambry internal data). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. - |
Likely pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 18, 2022 | - - |
Aplastic anemia;C0023449:Acute lymphoid leukemia;C0398791:Microcephaly, normal intelligence and immunodeficiency Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 23, 2024 | - - |
Aplastic anemia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 01, 2024 | - - |
Gastric cancer Pathogenic:1
Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at