rs746765533
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_001077350.3(NPRL3):c.318+3A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001077350.3 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000198 AC: 3AN: 151898Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000161 AC: 4AN: 248066Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 134630
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461110Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 726836
GnomAD4 genome AF: 0.0000198 AC: 3AN: 151898Hom.: 0 Cov.: 33 AF XY: 0.0000270 AC XY: 2AN XY: 74200
ClinVar
Submissions by phenotype
Epilepsy, familial focal, with variable foci 3 Uncertain:2Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Brain Gene Registry | - | This participant was tested at multiple clinical laboratories and the variant was classified as Uncertain significance at both laboratories. Variant most recently reported on 05-24-2021 by New York Genome Center and 02-23-2021 by Sema4. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. - |
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | May 24, 2021 | The inherited heterozygous splice region variant c.318+3A>T has not been reported in the literature in individuals with NPRL3-related disease. The variant affects a nucleotide within the consensus splice site of the intron 4 and is absent in the gnomAD v3.1.1 database, indicating a rare allele. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID:17576681; PMID:9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Still, this prediction has not been confirmed by published transcriptional studies. Based on the available evidence, the inherited variant c.318+3A>T in the NPRL3 gene is classified as a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 22, 2022 | 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. This sequence change falls in intron 4 of the NPRL3 gene. It does not directly change the encoded amino acid sequence of the NPRL3 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs746765533, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with NPRL3-related conditions. ClinVar contains an entry for this variant (Variation ID: 574218). 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 disrupt the consensus splice site. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 19, 2021 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 27535533) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at