16-110604-T-G

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.550A>C(p.Asn184His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00671 in 1,607,092 control chromosomes in the GnomAD database, including 145 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. N184N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.015 ( 43 hom., cov: 32)

Exomes 𝑓: 0.0058 ( 102 hom. )

Consequence

NPRL3
NM_001077350.3 missense, splice_region

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.04

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=0.0032077432).

BP6

Variant 16-110604-T-G is Benign according to our data. Variant chr16-110604-T-G is described in ClinVar as Benign. ClinVar VariationId is 476225.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 = 0.015 (2286/152270) while in subpopulation AFR AF = 0.0334 (1389/41556). AF 95% confidence interval is 0.032. There are 43 homozygotes in GnomAd4. There are 1202 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2286 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPRL3	NM_001077350.3 link	c.550A>C	p.Asn184His	missense_variant, splice_region_variant	Exon 7 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.550A>C	p.Asn184His	missense_variant, splice_region_variant	Exon 7 of 14	5	NM_001077350.3	ENSP00000478273.1		Q12980

Frequencies

GnomAD3 genomes

AF:

0.0150

AC:

2276

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0333

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.00668

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00270

Gnomad SAS

AF:

0.0126

Gnomad FIN

AF:

0.0372

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00395

Gnomad OTH

AF:

0.0153

GnomAD2 exomes

AF:

0.00927

AC:

2203

AN:

237606

AF XY:

0.00912

show subpopulations

Gnomad AFR exome

AF:

0.0317

Gnomad AMR exome

AF:

0.00421

Gnomad ASJ exome

AF:

0.00133

Gnomad EAS exome

AF:

0.000459

Gnomad FIN exome

AF:

0.0308

Gnomad NFE exome

AF:

0.00454

Gnomad OTH exome

AF:

0.00646

GnomAD4 exome

AF:

0.00584

AC:

8502

AN:

1454822

Hom.:

102

Cov.:

AF XY:

0.00613

AC XY:

4430

AN XY:

723038

show subpopulations

African (AFR)

AF:

0.0369

AC:

1230

AN:

33336

American (AMR)

AF:

0.00402

AC:

176

AN:

43824

Ashkenazi Jewish (ASJ)

AF:

0.00150

AC:

AN:

25926

East Asian (EAS)

AF:

0.000328

AC:

AN:

39602

South Asian (SAS)

AF:

0.0147

AC:

1244

AN:

84716

European-Finnish (FIN)

AF:

0.0303

AC:

1609

AN:

53036

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00328

AC:

3633

AN:

1108470

Other (OTH)

AF:

0.00830

AC:

499

AN:

60156

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

360

719

1079

1438

1798

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

312

468

624

780

<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:

0.0150

AC:

2286

AN:

152270

Hom.:

Cov.:

AF XY:

0.0161

AC XY:

1202

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0334

AC:

1389

AN:

41556

American (AMR)

AF:

0.00667

AC:

102

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3470

East Asian (EAS)

AF:

0.00271

AC:

AN:

5174

South Asian (SAS)

AF:

0.0126

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0372

AC:

395

AN:

10612

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00395

AC:

269

AN:

68022

Other (OTH)

AF:

0.0151

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

118

235

353

470

588

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.00750

Hom.:

Bravo

AF:

0.0130

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.0262

AC:

105

ESP6500EA

AF:

0.00289

AC:

ExAC

AF:

0.00963

AC:

1164

Asia WGS

AF:

0.0220

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Sep 14, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Epilepsy, familial focal, with variable foci 3

Benign:1

Feb 04, 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

0.063

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.093

T;.;T;.

Eigen

Benign

-0.038

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.84

T;T;.;T

MetaRNN

Benign

0.0032

T;T;T;T

MetaSVM

Benign

-1.1

PhyloP100

1.0

PrimateAI

Benign

0.38

REVEL

Benign

0.051

Sift4G

Benign

0.43

T;T;T;.

Polyphen

0.51

P;B;P;.

Vest4

0.15

MVP

0.18

MPC

0.26

ClinPred

0.0049

GERP RS

0.58

Varity_R

0.079

gMVP

0.22

Mutation Taster

=90/10

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