16-92716-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001077350.3(NPRL3):c.1041G>A(p.Pro347Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0301 in 1,613,346 control chromosomes in the GnomAD database, including 876 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 59 hom., cov: 32)

Exomes 𝑓: 0.031 ( 817 hom. )

Consequence

NPRL3
NM_001077350.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -4.07

Publications

6 publications found

Variant links:

COSMIC-nc: COSV67852271

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 16-92716-C-T is Benign according to our data. Variant chr16-92716-C-T is described in ClinVar as Benign. ClinVar VariationId is 476213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.07 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0199 (3035/152286) while in subpopulation NFE AF = 0.0355 (2414/68010). AF 95% confidence interval is 0.0343. There are 59 homozygotes in GnomAd4. There are 1380 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 3035 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPRL3	NM_001077350.3 link	c.1041G>A	p.Pro347Pro	synonymous_variant	Exon 11 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.1041G>A	p.Pro347Pro	synonymous_variant	Exon 11 of 14	5	NM_001077350.3	ENSP00000478273.1		Q12980

Frequencies

GnomAD3 genomes

AF:

0.0200

AC:

3038

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00521

Gnomad AMI

AF:

0.0318

Gnomad AMR

AF:

0.0109

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0108

Gnomad FIN

AF:

0.00933

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0355

Gnomad OTH

AF:

0.0129

GnomAD2 exomes

AF:

0.0200

AC:

4945

AN:

247548

AF XY:

0.0207

show subpopulations

Gnomad AFR exome

AF:

0.00601

Gnomad AMR exome

AF:

0.00948

Gnomad ASJ exome

AF:

0.0123

Gnomad EAS exome

AF:

0.000279

Gnomad FIN exome

AF:

0.0112

Gnomad NFE exome

AF:

0.0333

Gnomad OTH exome

AF:

0.0205

GnomAD4 exome

AF:

0.0311

AC:

45459

AN:

1461060

Hom.:

817

Cov.:

AF XY:

0.0303

AC XY:

21989

AN XY:

726736

show subpopulations

African (AFR)

AF:

0.00433

AC:

145

AN:

33472

American (AMR)

AF:

0.00918

AC:

410

AN:

44656

Ashkenazi Jewish (ASJ)

AF:

0.0111

AC:

289

AN:

26122

East Asian (EAS)

AF:

0.000781

AC:

AN:

39688

South Asian (SAS)

AF:

0.0102

AC:

875

AN:

86108

European-Finnish (FIN)

AF:

0.0113

AC:

605

AN:

53320

Middle Eastern (MID)

AF:

0.00642

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0374

AC:

41548

AN:

1111580

Other (OTH)

AF:

0.0252

AC:

1519

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

2346

4692

7038

9384

11730

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1548

3096

4644

6192

7740

<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:

0.0199

AC:

3035

AN:

152286

Hom.:

Cov.:

AF XY:

0.0185

AC XY:

1380

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00519

AC:

216

AN:

41580

American (AMR)

AF:

0.0109

AC:

166

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00893

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5180

South Asian (SAS)

AF:

0.0106

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00933

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0355

AC:

2414

AN:

68010

Other (OTH)

AF:

0.0123

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

151

303

454

606

757

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0301

Hom.:

147

Bravo

AF:

0.0198

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0324

EpiControl

AF:

0.0321

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 15, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

BayesDel_noAF

Benign

-0.60

CADD

Benign

4.7

(source)

DANN

Benign

0.58

PhyloP100

-4.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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