chr8-89978217-T-C
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_002485.5(NBN):c.584+3A>G variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.00000125 in 1,597,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
NBN
NM_002485.5 splice_donor_region, intron
NM_002485.5 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9996
2
Clinical Significance
Conservation
PhyloP100: 5.98
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 Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NBN | NM_002485.5 | c.584+3A>G | splice_donor_region_variant, intron_variant | ENST00000265433.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NBN | ENST00000265433.8 | c.584+3A>G | splice_donor_region_variant, intron_variant | 1 | NM_002485.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251122Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135776
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GnomAD4 exome AF: 6.92e-7 AC: 1AN: 1445600Hom.: 0 Cov.: 28 AF XY: 0.00000139 AC XY: 1AN XY: 720344
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74362
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Microcephaly, normal intelligence and immunodeficiency Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 28, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 27, 2022 | This sequence change falls in intron 5 of the NBN gene. It does not directly change the encoded amino acid sequence of the NBN protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs587782407, gnomAD 0.006%). 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: 142362). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 28, 2023 | The c.584+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 5 in the NBN gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive; however RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 27, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 17576681, 9536098) - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at