rs547498080
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2
The NM_001077350.3(NPRL3):c.1252G>A(p.Glu418Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000144 in 1,593,650 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00015 ( 0 hom. )
Consequence
NPRL3
NM_001077350.3 missense
NM_001077350.3 missense
Scores
5
11
Clinical Significance
Conservation
PhyloP100: 4.66
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 -6 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.4086155).
BP6
Variant 16-89812-C-T is Benign according to our data. Variant chr16-89812-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 476218.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.
BS2
High AC in GnomAd4 at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPRL3 | NM_001077350.3 | c.1252G>A | p.Glu418Lys | missense_variant | 12/14 | ENST00000611875.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPRL3 | ENST00000611875.5 | c.1252G>A | p.Glu418Lys | missense_variant | 12/14 | 5 | NM_001077350.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152202Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000122 AC: 26AN: 212510Hom.: 0 AF XY: 0.000129 AC XY: 15AN XY: 115892
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GnomAD4 exome AF: 0.000155 AC: 223AN: 1441448Hom.: 0 Cov.: 31 AF XY: 0.000154 AC XY: 110AN XY: 715550
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GnomAD4 genome AF: 0.0000460 AC: 7AN: 152202Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74352
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Epilepsy, familial focal, with variable foci 3 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 03, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 418 of the NPRL3 protein (p.Glu418Lys). This variant is present in population databases (rs547498080, gnomAD 0.02%). 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: 476218). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NPRL3 protein function with a negative predictive value of 80%. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Jan 12, 2022 | This variant has not been reported in the literature but is present in 0.008% (6/68020) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-89812-C-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:476218). Evolutionary conservation for this variant is unclear; computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 12, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2022 | NPRL3: PP4, BP4 - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 22, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
REVEL
Benign
Sift4G
Benign
T;T;T
Polyphen
D;P;D
Vest4
MutPred
Gain of sheet (P = 0.0043);.;Gain of sheet (P = 0.0043);
MVP
MPC
0.24
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at