Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001221547 | SCV001393599 | pathogenic | Nephronophthisis | 2022-10-17 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 17 of the NPHP4 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 NPHP4 are known to be pathogenic (PMID: 12205563, 23559409). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with clinical features of nephronophthisis (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 949949). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| 3billion | RCV002283531 | SCV002572723 | pathogenic | Nephronophthisis 4 | 2022-09-01 | criteria provided, single submitter | clinical testing | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Canonical splice site is predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported to be associated with NPHP4-related disorder (ClinVar ID: VCV000949949). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. |