Submissions for variant NR_023343.3(RNU4ATAC):n.48G>A

gnomAD frequency: 0.00005  dbSNP: rs863225422

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Undiagnosed Diseases Network, NIH	RCV000202314	SCV000837726	likely pathogenic	Roifman syndrome	2018-03-20	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001095783	SCV001251631	likely pathogenic	RNU4ATAC-related spliceosomopathies	2020-01-31	criteria provided, single submitter	clinical testing	The RNU4ATAC n.48G>A variant is a single nucleotide variant in a non-coding region which impacts the U4atac snRNA. The n.48G>A variant is reported in a compound heterozygous state in one individual with Roifman syndrome (Merico et al. 2015). Additionally, the n.48G>A variant is reported in a compound heterozygous state in a second individual with Roifman syndrome in a submission from the Undiagnosed Disease Network (UDN) to the ClinVar database (Landrum et al. 2018). Although not described in the published literature, additional information about this child is available on the UDN website (https://undiagnosed.hms.harvard.edu/participants/participant-127/ ). In both available cases, the n.48G>A variant was reported in trans with the n.13C>T variant. The n.48G>A variant is reported at a frequency of 0.000060 in the European (non-Finnish) population of the Genome Aggregation Database in a region of good sequence coverage so the variant is presumed to be rare. It is located in the kink-turn motif of the 5' stem loop of U4atac snRNA, which interacts with the human NHP2L1 protein during assembly of the minor spliceosome. While the consequences of the n.48G>A variant have not been evaluated experimentally, other variants in the kink-turn motif of the 5' stem loop and observed in individuals with Taybi Linder syndrome have been shown to impair binding to the NHP2L1 protein and minor spliceosome function (Jafarifar et al. 2014; Merico et al. 2015). Based on the collective evidence, the n.48G>A variant is classified as likely pathogenic for RNU4ATAC-related spliceosomopathies.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268112	SCV001446769	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001268112	SCV001747957	likely pathogenic	not provided	2021-03-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001268112	SCV002249758	pathogenic	not provided	2024-12-24	criteria provided, single submitter	clinical testing	This variant occurs in the RNU4ATAC gene, which encodes an RNA molecule that does not result in a protein product. This variant is present in population databases (no rsID available, gnomAD 0.02%). This variant has been observed in individual(s) with RNU4ATAC-related conditions and/or Roifman syndrome (PMID: 26522830; internal data). 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: 218085). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Functional studies have shown that this variant disrupts ncRNA splicing (PMID: 32628740). This variant is located within the 5' stem-loop region of the RNU4ATAC RNA, which includes the 15.5K binding site and is important for spliceosome assembly (PMID: 32628740). A significant number of disease-associated RNU4ATAC variants are found in this region (PMID: 32628740, 30368667). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002500634	SCV002808715	likely pathogenic	Osteodysplastic primordial dwarfism, type 1; Lowry-Wood syndrome; Roifman syndrome	2022-03-09	criteria provided, single submitter	clinical testing
OMIM	RCV000202314	SCV000257316	pathogenic	Roifman syndrome	2015-11-02	no assertion criteria provided	literature only
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV001255778	SCV001432378	likely pathogenic	Osteodysplastic primordial dwarfism, type 1		no assertion criteria provided	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003989502	SCV004807292	uncertain significance	Lowry-Wood syndrome	2024-03-26	flagged submission	clinical testing