Genetic Variant NM_001077350.3:c.1278C>G (chr16-89786-G-C) – ACMG Classification: Benign (-20 pts)

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.1278C>G(p.Asp426Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00408 in 1,600,348 control chromosomes in the GnomAD database, including 167 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D426D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.014 ( 71 hom., cov: 33)

Exomes 𝑓: 0.0030 ( 96 hom. )

Consequence

NPRL3
NM_001077350.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.50

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: Labcorp Genetics (formerly Invitae), Ambry Genetics
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=0.0017733276).

BP6

Variant 16-89786-G-C is Benign according to our data. Variant chr16-89786-G-C is described in ClinVar as Benign. ClinVar VariationId is 476219.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 = 0.0143 (2174/152342) while in subpopulation AFR AF = 0.0469 (1949/41572). AF 95% confidence interval is 0.0451. There are 71 homozygotes in GnomAd4. There are 1071 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 2174 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001077350.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NPRL3	NM_001077350.3	MANE Select	c.1278C>G	p.Asp426Glu	missense	Exon 12 of 14	NP_001070818.1	Q12980
NPRL3	NM_001243248.2		c.1203C>G	p.Asp401Glu	missense	Exon 11 of 13	NP_001230177.1	B7Z6Q0
NPRL3	NM_001243249.2		c.1203C>G	p.Asp401Glu	missense	Exon 10 of 12	NP_001230178.1	B7Z6Q0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NPRL3	ENST00000611875.5	TSL:5 MANE Select	c.1278C>G	p.Asp426Glu	missense	Exon 12 of 14	ENSP00000478273.1	Q12980
NPRL3	ENST00000399953.7	TSL:1	c.1203C>G	p.Asp401Glu	missense	Exon 10 of 12	ENSP00000382834.4	B7Z6Q0
NPRL3	ENST00000621703.4	TSL:1	n.*863C>G		non_coding_transcript_exon	Exon 9 of 11	ENSP00000477801.1	A0A087WTE2

Frequencies

GnomAD3 genomes

AF:

0.0142

AC:

2158

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0466

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00412

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0287

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00955

GnomAD2 exomes

AF:

0.00644

AC:

1452

AN:

225582

AF XY:

0.00647

show subpopulations

Gnomad AFR exome

AF:

0.0455

Gnomad AMR exome

AF:

0.00186

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000107

Gnomad OTH exome

AF:

0.00407

GnomAD4 exome

AF:

0.00301

AC:

4363

AN:

1448006

Hom.:

Cov.:

AF XY:

0.00354

AC XY:

2550

AN XY:

719750

show subpopulations

African (AFR)

AF:

0.0467

AC:

1527

AN:

32732

American (AMR)

AF:

0.00210

AC:

AN:

42896

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25676

East Asian (EAS)

AF:

0.00

AC:

AN:

38778

South Asian (SAS)

AF:

0.0277

AC:

2326

AN:

83970

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51332

Middle Eastern (MID)

AF:

0.00332

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.0000488

AC:

AN:

1107034

Other (OTH)

AF:

0.00580

AC:

347

AN:

59858

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

220

440

660

880

1100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

246

328

410

<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:

0.0143

AC:

2174

AN:

152342

Hom.:

Cov.:

AF XY:

0.0144

AC XY:

1071

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0469

AC:

1949

AN:

41572

American (AMR)

AF:

0.00412

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.0285

AC:

138

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68016

Other (OTH)

AF:

0.00945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

195

292

390

487

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:

0.000736

Hom.:

Bravo

AF:

0.0154

ESP6500AA

AF:

0.0382

AC:

166

ESP6500EA

AF:

0.000234

AC:

ExAC

AF:

0.00731

AC:

882

Asia WGS

AF:

0.0220

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

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

NPRL3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.0010

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.050

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.98

PhyloP100

-2.5

PrimateAI

Benign

0.45

REVEL

Benign

0.11

Sift4G

Benign

0.65

Polyphen

0.0

Vest4

0.24

MutPred

0.64

Gain of helix (P = 0.062)

MVP

0.21

MPC

0.20

ClinPred

0.0013

GERP RS

-9.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.095

gMVP

0.11

Mutation Taster

=94/6

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over