16-93226-C-T

Position:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001077350.3(NPRL3):​c.1024G>A​(p.Val342Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000194 in 1,549,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V342L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

NPRL3
NM_001077350.3 missense

Scores

1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.78
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.1270403).
BS2
High AC in GnomAdExome4 at 28 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NPRL3NM_001077350.3 linkuse as main transcriptc.1024G>A p.Val342Ile missense_variant 10/14 ENST00000611875.5 NP_001070818.1 Q12980Q9BTE2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NPRL3ENST00000611875.5 linkuse as main transcriptc.1024G>A p.Val342Ile missense_variant 10/145 NM_001077350.3 ENSP00000478273.1 Q12980

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152228
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000124
AC:
2
AN:
161568
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
85526
show subpopulations
Gnomad AFR exome
AF:
0.000118
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000155
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000200
AC:
28
AN:
1397292
Hom.:
0
Cov.:
30
AF XY:
0.0000159
AC XY:
11
AN XY:
689810
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000278
Gnomad4 SAS exome
AF:
0.0000631
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000186
Gnomad4 OTH exome
AF:
0.0000172
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152228
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74378
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000189
ExAC
AF:
0.0000182
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Epilepsy, familial focal, with variable foci 3 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 11, 2023This sequence change replaces valine with isoleucine at codon 342 of the NPRL3 protein (p.Val342Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs11558704, gnomAD 0.01%). 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: 652239). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.072
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.56
CADD
Benign
19
DANN
Benign
0.84
DEOGEN2
Benign
0.055
T;.;T
Eigen
Benign
-0.21
Eigen_PC
Benign
-0.058
FATHMM_MKL
Benign
0.74
D
LIST_S2
Uncertain
0.92
D;D;.
M_CAP
Benign
0.0033
T
MetaRNN
Benign
0.13
T;T;T
MetaSVM
Benign
-0.99
T
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-0.67
.;N;.
REVEL
Benign
0.11
Sift
Benign
0.16
.;T;.
Sift4G
Benign
0.96
T;T;T
Polyphen
0.0060
B;B;B
Vest4
0.090
MutPred
0.40
Loss of catalytic residue at V342 (P = 0.0877);.;Loss of catalytic residue at V342 (P = 0.0877);
MVP
0.44
MPC
0.18
ClinPred
0.63
D
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.17
gMVP
0.14

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs11558704; hg19: chr16-143224; API