chr8-89955537-TG-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_002485.5(NBN):βc.1142delβ(p.Pro381GlnfsTer23) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000539 in 1,613,320 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. P381P) 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.1142del | p.Pro381GlnfsTer23 | frameshift_variant | 10/16 | ENST00000265433.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NBN | ENST00000265433.8 | c.1142del | p.Pro381GlnfsTer23 | frameshift_variant | 10/16 | 1 | NM_002485.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000240 AC: 6AN: 249986Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135274
GnomAD4 exome AF: 0.0000575 AC: 84AN: 1461150Hom.: 0 Cov.: 33 AF XY: 0.0000495 AC XY: 36AN XY: 726894
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74330
ClinVar
Submissions by phenotype
Microcephaly, normal intelligence and immunodeficiency Pathogenic:7Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Mar 21, 2023 | The NBN c.1142del (p.Pro381GlnfsTer23) change deletes one nucleotide and causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay. This variant has a maximum subpopulation frequency of 0.0053% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant has been reported as compound heterozygous in an individuals affected with Nijmegen breakage syndrome (PMID: 9590180, 12621246). In addition, this variant has been identified in individuals with ovarian cancer (PMID: 22006311, 26315354, 29625052, 30322717). Two individuals with this variant are reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). In summary, this variant meets criteria to be classified as pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 1998 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change creates a premature translational stop signal (p.Pro381Glnfs*23) 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 (rs587781969, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with Nijmegen breakage syndrome (PMID: 9590180, 10799436, 12621246, 22006311, 24549055, 26315354). ClinVar contains an entry for this variant (Variation ID: 141731). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 14, 2020 | Variant summary: NBN c.1142delC (p.Pro381GlnfsX23) 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. The variant allele was found at a frequency of 2.4e-05 in 249986 control chromosomes (gnomAD). c.1142delC has been reported in the literature in multiple individuals affected with Nijmegen Breakage Syndrome (e.g. Bakshi_2003, Varon_1998) as well as in breast and/or ovarian cancer patients (Ramus_2015, Walsh_2011, Carter_2018). These data indicate that the variant is very likely to be associated with disease. No Nibrin protein expression was detected in a cell line derived from a compound heterozygous patient who harbored this variant and another truncating variant (Bakshi_2003). Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 16, 2017 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 22, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | NBN: PVS1, PM2 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 21, 2022 | Observed with a pathogenic founder variant in individuals with Nijmegen breakage syndrome in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (Varon et al., 1998; Bakhshi et al., 2003); 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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27038244, 22006311, 10799436, 24549055, 18593981, 26315354, 26270727, 15578693, 16033915, 10792024, 24072268, 28152038, 30322717, 30612635, 26689913, 33439686, 31589614, 29625052, 12621246, 9590180, 28888541, 29922827, 33804961, 36003761) - |
Aplastic anemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 24, 2024 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 15, 2021 | The c.1142delC pathogenic mutation, located in coding exon 10 of the NBN gene, results from a deletion of one nucleotide at nucleotide position 1142, causing a translational frameshift with a predicted alternate stop codon (p.P381Qfs*23). This alteration has been described in conjunction with a pathogenic founder mutation in at least one patient with Nijmegen breakage syndrome (Varon R et al. Cell. 1998 May;93:467-76). This alteration has also been reported in cohorts of patients with a personal and/or family history of breast and/or ovarian cancers (Walsh T et al. Proc. Natl. Acad. Sci. USA. 2011 Nov;108:18032-7; Castéra L et al. Eur. J. Hum. Genet. 2014 Nov;22:1305-13; Desmond A et al. JAMA Oncol. 2015 Oct;1:943-51; Lu C et al. Nat Commun. 2015 Dec 22;6:10086; Carter NJ et al. Gynecol Oncol. 2018 12;151:481-488). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at