rs746765533
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_001077350.3(NPRL3):c.318+3A>T variant causes a splice donor 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. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
NPRL3
NM_001077350.3 splice_donor_region, intron
NM_001077350.3 splice_donor_region, intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 3.21
Genes affected
NPRL3 (HGNC:14124): (NPR3 like, GATOR1 complex subunit) Contributes to GTPase activator activity. Involved in cellular response to amino acid starvation and negative regulation of TOR signaling. Located in lysosomal membrane. Part of GATOR1 complex. Implicated in focal epilepsy. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
BS2
?
High AC in GnomAdExome4 at 10 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPRL3 | NM_001077350.3 | c.318+3A>T | splice_donor_region_variant, intron_variant | ENST00000611875.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPRL3 | ENST00000611875.5 | c.318+3A>T | splice_donor_region_variant, intron_variant | 5 | NM_001077350.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000198 AC: 3AN: 151898Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000161 AC: 4AN: 248066Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 134630
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461110Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 726836
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GnomAD4 genome ? AF: 0.0000198 AC: 3AN: 151898Hom.: 0 Cov.: 33 AF XY: 0.0000270 AC XY: 2AN XY: 74200
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
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 | Invitae | 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. 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. ClinVar contains an entry for this variant (Variation ID: 574218). This variant has not been reported in the literature in individuals affected with NPRL3-related conditions. This variant is present in population databases (rs746765533, gnomAD 0.05%). 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. - |
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. - |
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
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at