16-86889-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001077350.3(NPRL3):c.1545-19A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.806 in 1,606,368 control chromosomes in the GnomAD database, including 524,519 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.75 ( 43468 hom., cov: 35)

Exomes 𝑓: 0.81 ( 481051 hom. )

Consequence

NPRL3
NM_001077350.3 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.820

Publications

14 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 (BayesDel_noAF=-0.82).

BP6

Variant 16-86889-T-C is Benign according to our data. Variant chr16-86889-T-C is described in ClinVar as Benign. ClinVar VariationId is 1631816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.808 is higher than 0.05.

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	Effect	Exon Rank	Protein
NPRL3	NM_001077350.3	MANE Select	c.1545-19A>G	intron	N/A	NP_001070818.1
NPRL3	NM_001243248.2		c.1470-19A>G	intron	N/A	NP_001230177.1
NPRL3	NM_001243249.2		c.1470-19A>G	intron	N/A	NP_001230178.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
NPRL3	ENST00000611875.5	TSL:5 MANE Select	c.1545-19A>G	intron	N/A	ENSP00000478273.1
NPRL3	ENST00000399953.7	TSL:1	c.1470-19A>G	intron	N/A	ENSP00000382834.4
NPRL3	ENST00000621703.4	TSL:1	n.*1130-19A>G	intron	N/A	ENSP00000477801.1

Frequencies

GnomAD3 genomes

AF:

0.750

AC:

114021

AN:

152084

Hom.:

43431

Cov.:

show subpopulations

Gnomad AFR

AF:

0.605

Gnomad AMI

AF:

0.719

Gnomad AMR

AF:

0.818

Gnomad ASJ

AF:

0.847

Gnomad EAS

AF:

0.721

Gnomad SAS

AF:

0.827

Gnomad FIN

AF:

0.748

Gnomad MID

AF:

0.775

Gnomad NFE

AF:

0.814

Gnomad OTH

AF:

0.764

GnomAD2 exomes

AF:

0.803

AC:

191126

AN:

237914

AF XY:

0.803

show subpopulations

Gnomad AFR exome

AF:

0.592

Gnomad AMR exome

AF:

0.888

Gnomad ASJ exome

AF:

0.839

Gnomad EAS exome

AF:

0.722

Gnomad FIN exome

AF:

0.754

Gnomad NFE exome

AF:

0.816

Gnomad OTH exome

AF:

0.806

GnomAD4 exome

AF:

0.812

AC:

1180772

AN:

1454166

Hom.:

481051

Cov.:

AF XY:

0.813

AC XY:

587168

AN XY:

722636

show subpopulations

African (AFR)

AF:

0.582

AC:

19408

AN:

33362

American (AMR)

AF:

0.879

AC:

38872

AN:

44216

Ashkenazi Jewish (ASJ)

AF:

0.840

AC:

21840

AN:

25994

East Asian (EAS)

AF:

0.724

AC:

28566

AN:

39462

South Asian (SAS)

AF:

0.837

AC:

71608

AN:

85574

European-Finnish (FIN)

AF:

0.757

AC:

39302

AN:

51908

Middle Eastern (MID)

AF:

0.779

AC:

4354

AN:

5586

European-Non Finnish (NFE)

AF:

0.821

AC:

909126

AN:

1107988

Other (OTH)

AF:

0.794

AC:

47696

AN:

60076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

9899

19797

29696

39594

49493

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20892

41784

62676

83568

104460

<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:

0.750

AC:

114107

AN:

152202

Hom.:

43468

Cov.:

AF XY:

0.749

AC XY:

55737

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.606

AC:

25136

AN:

41510

American (AMR)

AF:

0.818

AC:

12521

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.847

AC:

2940

AN:

3472

East Asian (EAS)

AF:

0.721

AC:

3734

AN:

5176

South Asian (SAS)

AF:

0.827

AC:

3991

AN:

4828

European-Finnish (FIN)

AF:

0.748

AC:

7928

AN:

10604

Middle Eastern (MID)

AF:

0.776

AC:

228

AN:

294

European-Non Finnish (NFE)

AF:

0.814

AC:

55357

AN:

68000

Other (OTH)

AF:

0.767

AC:

1619

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

1504

3008

4512

6016

7520

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

856

1712

2568

3424

4280

<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:

0.767

Hom.:

5522

Bravo

AF:

0.745

Asia WGS

AF:

0.779

AC:

2713

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 96% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 89. Only high quality variants are reported.

not provided

Benign:1

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.94

(source)

DANN

Benign

0.37

PhyloP100

-0.82

Mutation Taster

=100/0

polymorphism (auto)

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over