rs58036849

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A496A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.010 ( 28 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 30 hom. )

Consequence

NPRL3
NM_001077350.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.15

Publications

0 publications found

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]

NPRL3 Gene-Disease associations (from GenCC):

focal epilepsy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
epilepsy, familial focal, with variable foci 3
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
familial focal epilepsy with variable foci
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

NPRL3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1583 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPRL3	NM_001077350.3 link	c.1486G>A	p.Ala496Thr	missense_variant	Exon 13 of 14	ENST00000611875.5	NP_001070818.1	Q12980Q9BTE2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPRL3	ENST00000611875.5 link	c.1486G>A	p.Ala496Thr	missense_variant	Exon 13 of 14	5	NM_001077350.3	ENSP00000478273.1		Q12980

Frequencies

GnomAD3 genomes

AF:

0.0103

AC:

1574

AN:

152202

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00266

AC:

634

AN:

238788

AF XY:

0.00212

show subpopulations

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 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.:

Cov.:

AF XY:

0.00112

AC XY:

817

AN XY:

726884

show subpopulations

African (AFR)

AF:

0.0384

AC:

1287

AN:

33474

American (AMR)

AF:

0.00188

AC:

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39688

South Asian (SAS)

AF:

0.000197

AC:

AN:

86158

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53348

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000240

AC:

267

AN:

1111718

Other (OTH)

AF:

0.00215

AC:

130

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

186

279

372

465

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0104

AC:

1583

AN:

152320

Hom.:

Cov.:

AF XY:

0.0103

AC XY:

769

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0354

AC:

1471

AN:

41568

American (AMR)

AF:

0.00451

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68028

Other (OTH)

AF:

0.00995

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

168

252

336

420

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00818

Hom.:

Bravo

AF:

0.0124

ESP6500AA

AF:

0.0332

AC:

145

ESP6500EA

AF:

0.000234

AC:

ExAC

AF:

0.00319

AC:

386

Asia WGS

AF:

0.00173

AC:

AN:

3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jun 12, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 05, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

Epilepsy, familial focal, with variable foci 3

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

T;.;T

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.00079

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.89

D;D;.

MetaRNN

Benign

0.0042

T;T;T

MetaSVM

Benign

-1.0

PhyloP100

4.1

PrimateAI

Benign

0.41

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

GERP RS

4.5

Varity_R

0.11

gMVP

0.31

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over