rs202015937
Positions:
Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4BP6_Very_StrongBS1BS2
The NM_001077350.3(NPRL3):c.1516A>T(p.Asn506Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,613,032 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00081 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0014 ( 1 hom. )
Consequence
NPRL3
NM_001077350.3 missense
NM_001077350.3 missense
Scores
4
7
4
Clinical Significance
Conservation
PhyloP100: 7.76
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 Benign. Variant got -17 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.35745215).
BP6
?
Variant 16-88726-T-A is Benign according to our data. Variant chr16-88726-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 542804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88726-T-A is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000815 (124/152194) while in subpopulation NFE AF= 0.00148 (101/68040). AF 95% confidence interval is 0.00125. There are 0 homozygotes in gnomad4. There are 49 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 124 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPRL3 | NM_001077350.3 | c.1516A>T | p.Asn506Tyr | missense_variant | 13/14 | ENST00000611875.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPRL3 | ENST00000611875.5 | c.1516A>T | p.Asn506Tyr | missense_variant | 13/14 | 5 | NM_001077350.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000815 AC: 124AN: 152194Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000715 AC: 177AN: 247476Hom.: 1 AF XY: 0.000647 AC XY: 87AN XY: 134496
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GnomAD4 exome AF: 0.00144 AC: 2099AN: 1460838Hom.: 1 Cov.: 31 AF XY: 0.00139 AC XY: 1007AN XY: 726578
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GnomAD4 genome ? AF: 0.000815 AC: 124AN: 152194Hom.: 0 Cov.: 33 AF XY: 0.000659 AC XY: 49AN XY: 74344
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 30, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2023 | NPRL3: BS1 - |
Epilepsy, familial focal, with variable foci 3 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
T;.;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
Sift4G
Uncertain
T;T;T
Polyphen
D;.;D
Vest4
MVP
MPC
0.89
ClinPred
T
GERP RS
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