chr16-124197-A-G

Variant names:

• chr16-124197-A-G
• rs2541612
• NM_001077350.3:c.189-4942T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001077350.3(NPRL3):​c.189-4942T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0841 in 152,170 control chromosomes in the GnomAD database, including 1,789 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.084 (1789 hom., cov: 32)
• Consequence: NPRL3 NM_001077350.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0160
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPRL3	NM_001077350.3	c.189-4942T>C		intron_variant	Intron 3 of 13	ENST00000611875.5	NP_001070818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPRL3	ENST00000611875.5	c.189-4942T>C		intron_variant	Intron 3 of 13	5	NM_001077350.3	ENSP00000478273.1

Frequencies

GnomAD3 genomes AF: 0.0839 AC: 12763 AN: 152052 Hom.: 1787 Cov.: 32

Gnomad AFR AF: 0.289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0355

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.0598

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0841 AC: 12797 AN: 152170 Hom.: 1789 Cov.: 32 AF XY: 0.0814 AC XY: 6055 AN XY: 74430

African (AFR) AF: 0.289 AC: 11980 AN: 41402

American (AMR) AF: 0.0355 AC: 542 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.0112 AC: 54 AN: 4832

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10626

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.000985 AC: 67 AN: 68038

Other (OTH) AF: 0.0591 AC: 125 AN: 2114

Alfa AF: 0.0601 Hom.: 179

Bravo AF: 0.0963

Asia WGS AF: 0.0240 AC: 82 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.5
DANN	Benign	0.70
PhyloP100		-0.016
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs2541612; hg19: chr16-174196;