rs767454740
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_002485.5(NBN):βc.156_157delβ(p.Ser53CysfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000669 in 1,613,832 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. F52F) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_002485.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NBN | NM_002485.5 | c.156_157del | p.Ser53CysfsTer9 | frameshift_variant | 2/16 | ENST00000265433.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NBN | ENST00000265433.8 | c.156_157del | p.Ser53CysfsTer9 | frameshift_variant | 2/16 | 1 | NM_002485.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251418Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135882
GnomAD4 exome AF: 0.0000732 AC: 107AN: 1461648Hom.: 0 AF XY: 0.0000646 AC XY: 47AN XY: 727134
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74346
ClinVar
Submissions by phenotype
Microcephaly, normal intelligence and immunodeficiency Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | This sequence change creates a premature translational stop signal (p.Ser53Cysfs*9) 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 (rs767454740, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 24549055). ClinVar contains an entry for this variant (Variation ID: 371121). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 07, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 18, 2020 | This frameshift variant causes the premature termination of NBN protein synthesis. It has been reported in individuals affected with hereditary breast and/or ovarian cancer in the published literature (PMID: 24549055 (2014)). Therefore, the variant is classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 26, 2021 | Frameshift 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 a significant frequency in large population cohorts (Lek 2016); Observed in an individual with a personal and/or family history of breast and/or ovarian cancer (Castera 2014); This variant is associated with the following publications: (PMID: 29922827, 24549055, 31263571) - |
Aplastic anemia;C0023449:Acute lymphoid leukemia;C0398791:Microcephaly, normal intelligence and immunodeficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 31, 2022 | - - |
Aplastic anemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
Acute lymphoid leukemia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 12, 2016 | - - |
See cases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jun 26, 2021 | ACMG classification criteria: PVS1, PS4, PM2 - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 28, 2022 | The c.156_157delTT pathogenic mutation, located in coding exon 2 of the NBN gene, results from a deletion of two nucleotides between nucleotide positions 156 and 157, causing a translational frameshift with a predicted alternate stop codon (p.S53Cfs*9). This deletion has been reported in one high risk breast and/or ovarian cancer individual (Castéra L et al. Eur. J. Hum. Genet. 2014 Nov;22:1305-13). (Hu C et al. JAMA, 2018 06;319:2401-2409). (Byrjalsen A et al. PLoS Genet, 2020 12;16:e1009231). (Zuntini R et al. Int J Mol Sci, 2021 May;22:). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 11, 2016 | Variant summary: The variant of interest causes a frameshift mutation resulting in a predicted truncated NBN protein, a mechanism for disease. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121384, which does not exceed the predicted maximum expected allele frequency for a pathogenic NBN variant of 1/8000 for HBOC. The variant of interest has been reported in an affected individual via a publication that consisted of a cohort of HBOC individuals. The variant of interest has not been reported in clinical laboratories or databases. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at