rs756363734
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_ModeratePP3_StrongPP5
The NM_002485.5(NBN):c.2184+1G>T variant causes a splice donor change. The variant allele was found at a frequency of 0.00000434 in 1,613,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_002485.5 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NBN | NM_002485.5 | c.2184+1G>T | splice_donor_variant | ENST00000265433.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NBN | ENST00000265433.8 | c.2184+1G>T | splice_donor_variant | 1 | NM_002485.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152078Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251284Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135826
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461362Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727002
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152078Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74284
ClinVar
Submissions by phenotype
Microcephaly, normal intelligence and immunodeficiency Pathogenic:5
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change affects a donor splice site in intron 14 of the NBN gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (no rsID available, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 28888541, 30130155). ClinVar contains an entry for this variant (Variation ID: 233424). Studies have shown that disruption of this splice site results in skipping of exon 14, but is expected to preserve the integrity of the reading-frame (Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 14, 2023 | Variant summary: NBN c.2184+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 256404 control chromosomes (gnomAD and publication data). c.2184+1G>T has been reported in the literature in individuals affected with ovarian cancer, breast cancer or osteosarcoma (Lilyquist_2017, Zheng_2018, Mirabello_2020). These data indicate that the variant may be associated with disease. 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: 35654374, 29922827, 28888541, 32191290, 30130155). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | May 27, 2021 | The NBN c.2184+1G>T intronic change results from a a G to T substitution at the +1 position of intron 14 of the NBN gene. This variant is predicted to result in loss of the native splice donor site (PP3) and skipping of exon 14 has been confirmed by RNA studies (PVS1_Strong; internal data). This variant has a maximum subpopulation frequency of 0.012% in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/8-90955480-C-A?dataset=gnomad_r2_1). This variant is absent in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (https://whi.color.com/). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria: PVS1_Strong, PM2_Supporting, PP3. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 04, 2016 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 01, 2023 | Canonical splice site variant reported to result in aberrant splicing (ClinVar SCV000553125.7, SCV001737449.2), disrupting the critical MRE11 interaction domain (Damiola et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast or ovarian cancer (Lilyquist et al., 2017; Zheng et al., 2018); This variant is associated with the following publications: (PMID: 29922827, 28888541, 30130155, 24894818) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 04, 2019 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 18, 2023 | The c.2184+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 14 of the NBN gene. One study detected this alteration in 0/3030 pancreatic cancer cases and 2/123136 population controls (Hu C et al. JAMA, 2018 06;319:2401-2409). This alteration was detected in 1/1136 cases and 0/997 controls in a Nigeran breast cancer study (Zheng Y et al. J Clin Oncol, 2018 Oct;36:2820-2825), and was also detected in cohort of 1004 patients with osteosarcoma (Mirabello L et al. JAMA Oncol, 2020 May;6:724-734). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. - |
Aplastic anemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 19, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at