rs864622253
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_002485.5(NBN):βc.93_94delβ(p.Ala32HisfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,346 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ).
Frequency
Genomes: not found (cov: 32)
Exomes π: 0.0000041 ( 0 hom. )
Consequence
NBN
NM_002485.5 frameshift
NM_002485.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.99
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 248 pathogenic variants in the truncated region.
PP5
Variant 8-89982798-GCA-G is Pathogenic according to our data. Variant chr8-89982798-GCA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 219789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NBN | NM_002485.5 | c.93_94del | p.Ala32HisfsTer4 | frameshift_variant | 2/16 | ENST00000265433.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NBN | ENST00000265433.8 | c.93_94del | p.Ala32HisfsTer4 | frameshift_variant | 2/16 | 1 | NM_002485.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461346Hom.: 0 AF XY: 0.00000413 AC XY: 3AN XY: 727022
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GnomAD4 genome Cov.: 32
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32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Microcephaly, normal intelligence and immunodeficiency Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 15, 2023 | This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala32Hisfs*4) 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 premature translational stop signal has been observed in individual(s) with lung cancer (PMID: 9590180, 16415040, 27844240). ClinVar contains an entry for this variant (Variation ID: 219789). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 14, 2023 | 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 in large population cohorts (gnomAD); Observed in individuals with a personal history of lung cancer and leukemia (Marafie et al., 2017; de Smith et al., 2019); This variant is associated with the following publications: (PMID: 27844240, 30639082, 31102422) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 27, 2020 | This frameshift variant is predicted to cause the premature termination of NBN protein synthesis. It has been reported in an individual affected with lung cancer as well as an unaffected individual in the published literature (PMID: 27844240 (2016)). Based on the available information, we predict that the variant is likely pathogenic. - |
Aplastic anemia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 27, 2024 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 07, 2022 | The c.93_94delTG pathogenic mutation, located in coding exon 2 of the NBN gene, results from a deletion of 2 nucleotides at positions 93 and 94 causing a translational frameshift with a predicted alternate stop codon (p.A32HFS*4). This mutation was identified in a lung cancer proband via whole exome sequencing, and was subsequently identified in the proband's unaffected 55-year-old sibling (Marafie MJ et al. Fam. Cancer 2017 07;16(3):389-394). 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. - |
Lymphoma;C0346153:Familial cancer of breast;C3469524:Prostate cancer susceptibility Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpreted as Pathogenic and reported on 06-25-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at