rs751567476
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PP3_StrongPP5_Very_Strong
The NM_002485.5(NBN):c.481-2A>T variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00000489 in 1,430,462 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 Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000049 ( 0 hom. )
Consequence
NBN
NM_002485.5 splice_acceptor
NM_002485.5 splice_acceptor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 5.63
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 20 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 8-89978325-T-A is Pathogenic according to our data. Variant chr8-89978325-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 451148.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.481-2A>T | splice_acceptor_variant | ENST00000265433.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NBN | ENST00000265433.8 | c.481-2A>T | splice_acceptor_variant | 1 | NM_002485.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
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33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250980Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135688
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GnomAD4 exome AF: 0.00000489 AC: 7AN: 1430462Hom.: 0 Cov.: 27 AF XY: 0.00000561 AC XY: 4AN XY: 713278
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Microcephaly, normal intelligence and immunodeficiency Pathogenic:3
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | This sequence change affects an acceptor splice site in intron 4 of the NBN gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs751567476, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with NBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 451148). Studies have shown that disruption of this splice site results in skipping of exon 5 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 12, 2018 | Variant summary: NBN c.481-2A>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: Five predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 245872 control chromosomes. This frequency is not higher than expected for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (1.2e-05 vs 0.0025), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.481-2A>T in individuals affected with Nijmegen Breakage Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 03, 2022 | This variant disrupts a canonical splice-acceptor site and is predicted to interfere with normal NBN mRNA splicing. The frequency of this variant in the general population, 0.000012 (3/250980 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in a homozygous state in an individual with stomach cancer (PMID: 34251444 (2021)). Based on the available information, this variant is classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 03, 2023 | Canonical splice site variant predicted to result in a null allele 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 an individual with esophagogastric cancer (Ku et al., 2021); This variant is associated with the following publications: (PMID: 29922827, 16415040, 9590180, 34251444) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 10, 2024 | The c.481-2A>T intronic variant results from an A to T substitution two nucleotides upstream from coding exon 5 in the NBN gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (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. - |
Likely pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 06, 2020 | - - |
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 | Jan 13, 2022 | - - |
Aplastic anemia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 12, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -41
DS_AL_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at