rs11558704

Variant names:

• chr16-93226-C-A
• rs11558704
• NM_001077350.3:c.1024G>T

Your query was ambiguous. Multiple possible variants found:

• chr16-93226-C-A
• chr16-93226-C-G
• chr16-93226-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001077350.3(NPRL3):​c.1024G>T​(p.Val342Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 1,549,608 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V342I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (10 hom.)
• Consequence: NPRL3 NM_001077350.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.78
• Publications: 7 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008386016).
• BP6: Variant 16-93226-C-A is Benign according to our data. Variant chr16-93226-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 542809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00167 (254/152346) while in subpopulation NFE AF = 0.00232 (158/68034). AF 95% confidence interval is 0.00203. There are 0 homozygotes in GnomAd4. There are 125 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 254 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPRL3	NM_001077350.3	MANE Select	c.1024G>T	p.Val342Leu	missense	Exon 10 of 14	NP_001070818.1	Q12980
	NPRL3	NM_001243248.2		c.949G>T	p.Val317Leu	missense	Exon 9 of 13	NP_001230177.1	B7Z6Q0
	NPRL3	NM_001243249.2		c.949G>T	p.Val317Leu	missense	Exon 8 of 12	NP_001230178.1	B7Z6Q0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPRL3	ENST00000611875.5	TSL:5 MANE Select	c.1024G>T	p.Val342Leu	missense	Exon 10 of 14	ENSP00000478273.1	Q12980
	NPRL3	ENST00000399953.7	TSL:1	c.949G>T	p.Val317Leu	missense	Exon 8 of 12	ENSP00000382834.4	B7Z6Q0
	NPRL3	ENST00000621703.4	TSL:1	n.*609G>T		non_coding_transcript_exon	Exon 7 of 11	ENSP00000477801.1	A0A087WTE2

Frequencies

GnomAD3 genomes AF: 0.00167 AC: 254 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00612

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00232

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00177 AC: 286 AN: 161568 AF XY: 0.00160

Gnomad AFR exome AF: 0.000237

Gnomad AMR exome AF: 0.000481

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00733

Gnomad NFE exome AF: 0.00198

Gnomad OTH exome AF: 0.00155

GnomAD4 exome AF: 0.00229 AC: 3200 AN: 1397262 Hom.: 10 Cov.: 30 AF XY: 0.00222 AC XY: 1534 AN XY: 689796

African (AFR) AF: 0.000380 AC: 12 AN: 31608

American (AMR) AF: 0.000417 AC: 15 AN: 35938

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25206

East Asian (EAS) AF: 0.00 AC: 0 AN: 35916

South Asian (SAS) AF: 0.000681 AC: 54 AN: 79262

European-Finnish (FIN) AF: 0.00792 AC: 392 AN: 49518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 0.00246 AC: 2651 AN: 1076078

Other (OTH) AF: 0.00131 AC: 76 AN: 58062

GnomAD4 genome AF: 0.00167 AC: 254 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.00168 AC XY: 125 AN XY: 74506

African (AFR) AF: 0.000505 AC: 21 AN: 41578

American (AMR) AF: 0.000261 AC: 4 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00612 AC: 65 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00232 AC: 158 AN: 68034

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00176 Hom.: 0

Bravo AF: 0.00111

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000239 AC: 1

ESP6500EA AF: 0.00215 AC: 18

ExAC AF: 0.00132 AC: 145

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Epilepsy, familial focal, with variable foci 3 (2)
-	-	1	NPRL3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Benign	0.35
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.088
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.12
Sift	Benign	0.058	T
Sift4G	Benign	0.69	T
Polyphen		0.062	B
Vest4		0.078
MutPred		0.39		Gain of helix (P = 0.132)
MVP		0.38
MPC		0.22
ClinPred		0.034	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.33
gMVP		0.28
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs11558704; hg19: chr16-143224; COSMIC: COSV105335024; COSMIC: COSV105335024;