16-92716-C-T

Variant names:

• chr16-92716-C-T
• rs1128426
• NM_001077350.3:c.1041G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001077350.3(NPRL3):​c.1041G>A​(p.Pro347Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0301 in 1,613,346 control chromosomes in the GnomAD database, including 876 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (59 hom., cov: 32)
  • Exomes 𝑓: 0.031 (817 hom.)
• Consequence: NPRL3 NM_001077350.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.07
• Publications: 6 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial focal epilepsy with variable foci

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 16-92716-C-T is Benign according to our data. Variant chr16-92716-C-T is described in ClinVar as Benign. ClinVar VariationId is 476213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.07 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0199 (3035/152286) while in subpopulation NFE AF = 0.0355 (2414/68010). AF 95% confidence interval is 0.0343. There are 59 homozygotes in GnomAd4. There are 1380 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3035 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.1041G>A	p.Pro347Pro	synonymous	Exon 11 of 14	NP_001070818.1
	NPRL3	NM_001243248.2		c.966G>A	p.Pro322Pro	synonymous	Exon 10 of 13	NP_001230177.1
	NPRL3	NM_001243249.2		c.966G>A	p.Pro322Pro	synonymous	Exon 9 of 12	NP_001230178.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPRL3	ENST00000611875.5	TSL:5 MANE Select	c.1041G>A	p.Pro347Pro	synonymous	Exon 11 of 14	ENSP00000478273.1
	NPRL3	ENST00000399953.7	TSL:1	c.966G>A	p.Pro322Pro	synonymous	Exon 9 of 12	ENSP00000382834.4
	NPRL3	ENST00000621703.4	TSL:1	n.*626G>A		non_coding_transcript_exon	Exon 8 of 11	ENSP00000477801.1

Frequencies

GnomAD3 genomes AF: 0.0200 AC: 3038 AN: 152168 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.00521

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.00933

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0355

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.0200 AC: 4945 AN: 247548 AF XY: 0.0207

Gnomad AFR exome AF: 0.00601

Gnomad AMR exome AF: 0.00948

Gnomad ASJ exome AF: 0.0123

Gnomad EAS exome AF: 0.000279

Gnomad FIN exome AF: 0.0112

Gnomad NFE exome AF: 0.0333

Gnomad OTH exome AF: 0.0205

GnomAD4 exome AF: 0.0311 AC: 45459 AN: 1461060 Hom.: 817 Cov.: 32 AF XY: 0.0303 AC XY: 21989 AN XY: 726736

African (AFR) AF: 0.00433 AC: 145 AN: 33472

American (AMR) AF: 0.00918 AC: 410 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.0111 AC: 289 AN: 26122

East Asian (EAS) AF: 0.000781 AC: 31 AN: 39688

South Asian (SAS) AF: 0.0102 AC: 875 AN: 86108

European-Finnish (FIN) AF: 0.0113 AC: 605 AN: 53320

Middle Eastern (MID) AF: 0.00642 AC: 37 AN: 5766

European-Non Finnish (NFE) AF: 0.0374 AC: 41548 AN: 1111580

Other (OTH) AF: 0.0252 AC: 1519 AN: 60348

GnomAD4 genome AF: 0.0199 AC: 3035 AN: 152286 Hom.: 59 Cov.: 32 AF XY: 0.0185 AC XY: 1380 AN XY: 74456

African (AFR) AF: 0.00519 AC: 216 AN: 41580

American (AMR) AF: 0.0109 AC: 166 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.0106 AC: 51 AN: 4822

European-Finnish (FIN) AF: 0.00933 AC: 99 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0355 AC: 2414 AN: 68010

Other (OTH) AF: 0.0123 AC: 26 AN: 2112

Alfa AF: 0.0301 Hom.: 147

Bravo AF: 0.0198

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0324

EpiControl AF: 0.0321

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	4.7
DANN	Benign	0.58
PhyloP100		-4.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1128426; hg19: chr16-142714; COSMIC: COSV67852271;