16-89786-G-C

Position:

• chr16-89786-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001077350.3(NPRL3):​c.1278C>G​(p.Asp426Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00408 in 1,600,348 control chromosomes in the GnomAD database, including 167 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D426D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.014 (71 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (96 hom.)
• Consequence: NPRL3 NM_001077350.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.50

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017733276).
• BP6: Variant 16-89786-G-C is Benign according to our data. Variant chr16-89786-G-C is described in ClinVar as [Benign]. Clinvar id is 476219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0143 (2174/152342) while in subpopulation AFR AF= 0.0469 (1949/41572). AF 95% confidence interval is 0.0451. There are 71 homozygotes in gnomad4. There are 1071 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2174 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPRL3	NM_001077350.3	c.1278C>G	p.Asp426Glu	missense_variant	12/14	ENST00000611875.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPRL3	ENST00000611875.5	c.1278C>G	p.Asp426Glu	missense_variant	12/14	5	NM_001077350.3	P1

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2158 AN: 152224 Hom.: 70 Cov.: 33

Gnomad AFR AF: 0.0466

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0287

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00644 AC: 1452 AN: 225582 Hom.: 29 AF XY: 0.00647 AC XY: 800 AN XY: 123564

Gnomad AFR exome AF: 0.0455

Gnomad AMR exome AF: 0.00186

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0277

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.00407

GnomAD4 exome AF: 0.00301 AC: 4363 AN: 1448006 Hom.: 96 Cov.: 31 AF XY: 0.00354 AC XY: 2550 AN XY: 719750

Gnomad4 AFR exome AF: 0.0467

Gnomad4 AMR exome AF: 0.00210

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0277

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000488

Gnomad4 OTH exome AF: 0.00580

GnomAD4 genome AF: 0.0143 AC: 2174 AN: 152342 Hom.: 71 Cov.: 33 AF XY: 0.0144 AC XY: 1071 AN XY: 74492

Gnomad4 AFR AF: 0.0469

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0285

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.000736 Hom.: 0

Bravo AF: 0.0154

ESP6500AA AF: 0.0382 AC: 166

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.00731 AC: 882

Asia WGS AF: 0.0220 AC: 75 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 18, 2019

- -

NPRL3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 13, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Epilepsy, familial focal, with variable foci 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.0010
DANN	Benign	0.58
DEOGEN2	Benign	0.050	T;.;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.68	T;T;.
MetaRNN	Benign	0.0018	T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.45	T
Sift4G	Benign	0.65	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.24
MutPred		0.64		Gain of helix (P = 0.062);.;Gain of helix (P = 0.062);
MVP		0.21
MPC		0.20
ClinPred		0.0013	T
GERP RS		-9.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.095
gMVP		0.11

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

Other links and lift over

dbSNP: rs74712570; hg19: chr16-139784;