Variant summary

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

The ENST00000611875.5(NPRL3):c.1356C>T(p.Ser452Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,609,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

NPRL3
ENST00000611875.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.63

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 16-88886-G-A is Benign according to our data. Variant chr16-88886-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 542808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.63 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000177 (258/1456948) while in subpopulation MID AF = 0.0108 (62/5754). AF 95% confidence interval is 0.00863. There are 0 homozygotes in GnomAdExome4. There are 128 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 22 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.1356C>T	p.Ser452Ser	synonymous	Exon 13 of 14	NP_001070818.1
NPRL3	NM_001243248.2		c.1281C>T	p.Ser427Ser	synonymous	Exon 12 of 13	NP_001230177.1
NPRL3	NM_001243249.2		c.1281C>T	p.Ser427Ser	synonymous	Exon 11 of 12	NP_001230178.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NPRL3	ENST00000611875.5	TSL:5 MANE Select	c.1356C>T	p.Ser452Ser	synonymous	Exon 13 of 14	ENSP00000478273.1
NPRL3	ENST00000399953.7	TSL:1	c.1281C>T	p.Ser427Ser	synonymous	Exon 11 of 12	ENSP00000382834.4
NPRL3	ENST00000621703.4	TSL:1	n.*941C>T		non_coding_transcript_exon	Exon 10 of 11	ENSP00000477801.1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000194

AC:

AN:

247524

AF XY:

0.000216

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000873

Gnomad ASJ exome

AF:

0.00160

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000205

Gnomad OTH exome

AF:

0.000832

GnomAD4 exome

AF:

0.000177

AC:

258

AN:

1456948

Hom.:

Cov.:

AF XY:

0.000177

AC XY:

128

AN XY:

723704

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33414

American (AMR)

AF:

0.0000673

AC:

AN:

44596

Ashkenazi Jewish (ASJ)

AF:

0.00196

AC:

AN:

26066

East Asian (EAS)

AF:

0.00

AC:

AN:

39550

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86098

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53332

Middle Eastern (MID)

AF:

0.0108

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000105

AC:

116

AN:

1107988

Other (OTH)

AF:

0.000382

AC:

AN:

60150

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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:

0.000145

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41456

American (AMR)

AF:

0.000131

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68034

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000311

Hom.:

Bravo

AF:

0.000185

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.55

PhyloP100

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over