rs58036849

Positions:

• chr16-88756-C-T

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.1486G>A​(p.Ala496Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00209 in 1,613,600 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (28 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (30 hom.)
• Consequence: NPRL3 NM_001077350.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.15

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=0.0042395294).
• BP6: Variant 16-88756-C-T is Benign according to our data. Variant chr16-88756-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445596.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 = 0.0104 (1583/152320) while in subpopulation AFR AF= 0.0354 (1471/41568). AF 95% confidence interval is 0.0339. There are 28 homozygotes in gnomad4. There are 769 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1583 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPRL3	NM_001077350.3	c.1486G>A	p.Ala496Thr	missense_variant	13/14	ENST00000611875.5	NP_001070818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPRL3	ENST00000611875.5	c.1486G>A	p.Ala496Thr	missense_variant	13/14	5	NM_001077350.3	ENSP00000478273	P1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1574 AN: 152202 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.0353

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00451

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0101

GnomAD3 exomes AF: 0.00266 AC: 634 AN: 238788 Hom.: 15 AF XY: 0.00212 AC XY: 275 AN XY: 129646

Gnomad AFR exome AF: 0.0366

Gnomad AMR exome AF: 0.00183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000241

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000249

Gnomad OTH exome AF: 0.000863

GnomAD4 exome AF: 0.00123 AC: 1797 AN: 1461280 Hom.: 30 Cov.: 31 AF XY: 0.00112 AC XY: 817 AN XY: 726884

Gnomad4 AFR exome AF: 0.0384

Gnomad4 AMR exome AF: 0.00188

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000240

Gnomad4 OTH exome AF: 0.00215

GnomAD4 genome AF: 0.0104 AC: 1583 AN: 152320 Hom.: 28 Cov.: 33 AF XY: 0.0103 AC XY: 769 AN XY: 74482

Gnomad4 AFR AF: 0.0354

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00995

Alfa AF: 0.00529 Hom.: 7

Bravo AF: 0.0124

ESP6500AA AF: 0.0332 AC: 145

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.00319 AC: 386

Asia WGS AF: 0.00173 AC: 6 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2021	Not observed in large population cohorts (Lek et al., 2016) In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function Has not been previously published as pathogenic or benign to our knowledge Observed in heterozygous state in multiple clinically unaffected adult relatives of individuals referred for genetic testing at GeneDx, suggesting the variant is benign -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 12, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.00079
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.89	D;D;.
MetaRNN	Benign	0.0042	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.52	D;D;D
PrimateAI	Benign	0.41	T
REVEL	Benign	0.060
Sift4G	Benign	0.56	T;T;T
Polyphen		0.0010	B;.;B
Vest4		0.28
MVP		0.39
MPC		0.24
ClinPred		0.0094	T
GERP RS		4.5
Varity_R		0.11
gMVP		0.31

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: rs58036849; hg19: chr16-138755;