16-89796-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The ENST00000611875.5(NPRL3):c.1268C>A(p.Pro423Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 1,599,042 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P423L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 1 hom. )

Consequence

NPRL3
ENST00000611875.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.407

Publications

2 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.043105006).

BP6

Variant 16-89796-G-T is Benign according to our data. Variant chr16-89796-G-T is described in ClinVar as Benign. ClinVar VariationId is 1443256.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 21 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000611875.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NPRL3	NM_001077350.3	MANE Select	c.1268C>A	p.Pro423Gln	missense	Exon 12 of 14	NP_001070818.1
NPRL3	NM_001243248.2		c.1193C>A	p.Pro398Gln	missense	Exon 11 of 13	NP_001230177.1
NPRL3	NM_001243249.2		c.1193C>A	p.Pro398Gln	missense	Exon 10 of 12	NP_001230178.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NPRL3	ENST00000611875.5	TSL:5 MANE Select	c.1268C>A	p.Pro423Gln	missense	Exon 12 of 14	ENSP00000478273.1
NPRL3	ENST00000399953.7	TSL:1	c.1193C>A	p.Pro398Gln	missense	Exon 10 of 12	ENSP00000382834.4
NPRL3	ENST00000621703.4	TSL:1	n.*853C>A		non_coding_transcript_exon	Exon 9 of 11	ENSP00000477801.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000225

AC:

AN:

222560

AF XY:

0.0000329

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000145

AC:

AN:

1446708

Hom.:

Cov.:

AF XY:

0.0000223

AC XY:

AN XY:

718858

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32800

American (AMR)

AF:

0.00

AC:

AN:

42662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25654

East Asian (EAS)

AF:

0.00

AC:

AN:

38704

South Asian (SAS)

AF:

0.000251

AC:

AN:

83638

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106304

Other (OTH)

AF:

0.00

AC:

AN:

59828

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000656

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41562

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000166

AC:

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Epilepsy, familial focal, with variable foci 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.58

CADD

Benign

2.9

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.047

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.84

M_CAP

Benign

0.011

MetaRNN

Benign

0.043

MetaSVM

Benign

-1.0

PhyloP100

0.41

PrimateAI

Benign

0.28

REVEL

Benign

0.074

Sift4G

Benign

0.61

Polyphen

0.052

Vest4

0.35

MutPred

0.52

Loss of glycosylation at P423 (P = 0.0273)

MVP

0.076

MPC

0.22

ClinPred

0.023

GERP RS

-1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.062

gMVP

0.13

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over