Genetic Variant NPRL3:p.Gly60Gly (chr16-130530-G-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_001077350.3(NPRL3):c.180C>A(p.Gly60Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G60G) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NPRL3
NM_001077350.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.84

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP7

Synonymous conserved (PhyloP=-1.84 with no splicing effect.

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.180C>A	p.Gly60Gly	synonymous	Exon 3 of 14	NP_001070818.1	Q12980
NPRL3	NM_001243248.2		c.180C>A	p.Gly60Gly	synonymous	Exon 3 of 13	NP_001230177.1	B7Z6Q0
NPRL3	NM_001243249.2		c.180C>A	p.Gly60Gly	synonymous	Exon 2 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.180C>A	p.Gly60Gly	synonymous	Exon 3 of 14	ENSP00000478273.1	Q12980
NPRL3	ENST00000399953.7	TSL:1	c.180C>A	p.Gly60Gly	synonymous	Exon 2 of 12	ENSP00000382834.4	B7Z6Q0
NPRL3	ENST00000621703.4	TSL:1	n.180C>A		non_coding_transcript_exon	Exon 2 of 11	ENSP00000477801.1	A0A087WTE2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1399690

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

690656

African (AFR)

AF:

0.00

AC:

AN:

31718

American (AMR)

AF:

0.00

AC:

AN:

35922

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25288

East Asian (EAS)

AF:

0.00

AC:

AN:

35930

South Asian (SAS)

AF:

0.00

AC:

AN:

79382

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47944

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5668

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079740

Other (OTH)

AF:

0.00

AC:

AN:

58098

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.14

(source)

DANN

Benign

0.87

PhyloP100

-1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over