ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.171+3A>G (rs1487002693)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Health, Inc RCV000580790 SCV000685733 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-13 criteria provided, single submitter clinical testing
Ambry Genetics RCV000580790 SCV001173346 pathogenic Hereditary cancer-predisposing syndrome 2019-11-26 criteria provided, single submitter clinical testing The c.171+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 2 in the NBN gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of 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). 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.
Invitae RCV001229330 SCV001401772 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2020-03-27 criteria provided, single submitter clinical testing This sequence change falls in intron 2 of the NBN gene. It does not directly change the encoded amino acid sequence of the NBN protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 490048). Nucleotide substitutions within 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 disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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