Submissions for variant NM_002485.5(NBN):c.163_171+3del

dbSNP: rs1057516772

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409755	SCV000486201	likely pathogenic	Microcephaly, normal intelligence and immunodeficiency	2016-04-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000566032	SCV000662689	pathogenic	Hereditary cancer-predisposing syndrome	2019-11-06	criteria provided, single submitter	clinical testing	The c.163_171+3del12 variant results from a deletion of 12 coding nucleotides at the 3' end of coding exon 2 in the NBN gene. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken this 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 due to an abnormal transcript, a translational frameshift leading to premature truncation, or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000409755	SCV000940767	likely pathogenic	Microcephaly, normal intelligence and immunodeficiency	2022-03-30	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 370793). This variant has not been reported in the literature in individuals affected with NBN-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant results in the deletion of part of exon 2 (c.163_171+3del) of the NBN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NBN are known to be pathogenic (PMID: 9590180, 16415040).
Genome-Nilou Lab	RCV000409755	SCV002045378	pathogenic	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003475956	SCV004199681	likely pathogenic	Aplastic anemia	2023-04-04	criteria provided, single submitter	clinical testing
GeneDx	RCV004591137	SCV005079668	likely pathogenic	not provided	2024-03-20	criteria provided, single submitter	clinical testing	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); This variant is associated with the following publications: (PMID: 34933735, 37453313, 29760218)