16-86889-T-C

Variant names:

• chr16-86889-T-C
• rs743725
• NM_001077350.3:c.1545-19A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001077350.3(NPRL3):​c.1545-19A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.806 in 1,606,368 control chromosomes in the GnomAD database, including 524,519 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43468 hom., cov: 35)
  • Exomes 𝑓: 0.81 (481051 hom.)
• Consequence: NPRL3 NM_001077350.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.820

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-86889-T-C is Benign according to our data. Variant chr16-86889-T-C is described in ClinVar as [Benign]. Clinvar id is 1631816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.808 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPRL3	NM_001077350.3	c.1545-19A>G		intron_variant	Intron 13 of 13	ENST00000611875.5	NP_001070818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPRL3	ENST00000611875.5	c.1545-19A>G		intron_variant	Intron 13 of 13	5	NM_001077350.3	ENSP00000478273.1

Frequencies

GnomAD3 genomes AF: 0.750 AC: 114021 AN: 152084 Hom.: 43431 Cov.: 35

Gnomad AFR AF: 0.605

Gnomad AMI AF: 0.719

Gnomad AMR AF: 0.818

Gnomad ASJ AF: 0.847

Gnomad EAS AF: 0.721

Gnomad SAS AF: 0.827

Gnomad FIN AF: 0.748

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.814

Gnomad OTH AF: 0.764

GnomAD3 exomes AF: 0.803 AC: 191126 AN: 237914 Hom.: 77391 AF XY: 0.803 AC XY: 104358 AN XY: 129918

Gnomad AFR exome AF: 0.592

Gnomad AMR exome AF: 0.888

Gnomad ASJ exome AF: 0.839

Gnomad EAS exome AF: 0.722

Gnomad SAS exome AF: 0.833

Gnomad FIN exome AF: 0.754

Gnomad NFE exome AF: 0.816

Gnomad OTH exome AF: 0.806

GnomAD4 exome AF: 0.812 AC: 1180772 AN: 1454166 Hom.: 481051 Cov.: 39 AF XY: 0.813 AC XY: 587168 AN XY: 722636

Gnomad4 AFR exome AF: 0.582

Gnomad4 AMR exome AF: 0.879

Gnomad4 ASJ exome AF: 0.840

Gnomad4 EAS exome AF: 0.724

Gnomad4 SAS exome AF: 0.837

Gnomad4 FIN exome AF: 0.757

Gnomad4 NFE exome AF: 0.821

Gnomad4 OTH exome AF: 0.794

GnomAD4 genome AF: 0.750 AC: 114107 AN: 152202 Hom.: 43468 Cov.: 35 AF XY: 0.749 AC XY: 55737 AN XY: 74422

Gnomad4 AFR AF: 0.606

Gnomad4 AMR AF: 0.818

Gnomad4 ASJ AF: 0.847

Gnomad4 EAS AF: 0.721

Gnomad4 SAS AF: 0.827

Gnomad4 FIN AF: 0.748

Gnomad4 NFE AF: 0.814

Gnomad4 OTH AF: 0.767

Alfa AF: 0.767 Hom.: 5522

Bravo AF: 0.745

Asia WGS AF: 0.779 AC: 2713 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 96% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 89. Only high quality variants are reported. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Epilepsy, familial focal, with variable foci 3 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.94
DANN	Benign	0.37

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

LitVar

Other links and lift over

dbSNP: rs743725; hg19: chr16-136888;