dbSNP rs114328109: NPRL3:c.*75G>A (chr16-86630-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001077350.3(NPRL3):c.*75G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000866 in 1,430,440 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0046 ( 6 hom., cov: 34)

Exomes 𝑓: 0.00042 ( 2 hom. )

Consequence

NPRL3
NM_001077350.3 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.51

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 16-86630-C-T is Benign according to our data. Variant chr16-86630-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1187214.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00461 (702/152296) while in subpopulation AFR AF = 0.0159 (661/41572). AF 95% confidence interval is 0.0149. There are 6 homozygotes in GnomAd4. There are 348 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High AC in GnomAd4 at 702 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	Effect	Exon Rank	Protein	UniProt
NPRL3	NM_001077350.3	MANE Select	c.*75G>A	3_prime_UTR	Exon 14 of 14	NP_001070818.1	Q12980
NPRL3	NM_001243248.2		c.*75G>A	3_prime_UTR	Exon 13 of 13	NP_001230177.1	B7Z6Q0
NPRL3	NM_001243249.2		c.*75G>A	3_prime_UTR	Exon 12 of 12	NP_001230178.1	B7Z6Q0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NPRL3	ENST00000611875.5	TSL:5 MANE Select	c.*75G>A	3_prime_UTR	Exon 14 of 14	ENSP00000478273.1	Q12980
NPRL3	ENST00000399953.7	TSL:1	c.*75G>A	3_prime_UTR	Exon 12 of 12	ENSP00000382834.4	B7Z6Q0
NPRL3	ENST00000621703.4	TSL:1	n.*1370G>A	non_coding_transcript_exon	Exon 11 of 11	ENSP00000477801.1	A0A087WTE2

Frequencies

GnomAD3 genomes

AF:

0.00461

AC:

702

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00239

GnomAD4 exome

AF:

0.000420

AC:

537

AN:

1278144

Hom.:

Cov.:

AF XY:

0.000386

AC XY:

242

AN XY:

626758

show subpopulations

African (AFR)

AF:

0.0155

AC:

456

AN:

29370

American (AMR)

AF:

0.000633

AC:

AN:

31602

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21950

East Asian (EAS)

AF:

0.00

AC:

AN:

34732

South Asian (SAS)

AF:

0.0000278

AC:

AN:

71818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33938

Middle Eastern (MID)

AF:

0.000263

AC:

AN:

3796

European-Non Finnish (NFE)

AF:

0.00000702

AC:

AN:

997360

Other (OTH)

AF:

0.000952

AC:

AN:

53578

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

100

125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00461

AC:

702

AN:

152296

Hom.:

Cov.:

AF XY:

0.00467

AC XY:

348

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0159

AC:

661

AN:

41572

American (AMR)

AF:

0.00203

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68010

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

104

138

173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000585

Hom.:

Bravo

AF:

0.00547

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.43

(source)

DANN

Benign

0.53

PhyloP100

-1.5

Mutation Taster

=100/0

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