rs1555439541

Variant names:

• chr16-88724-GTTCT-AGCCCCAGAA
• rs1555439541
• NM_001077350.3:c.1514_1518delAGAACinsTTCTGGGGCT

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001077350.3(NPRL3):​c.1514_1518delAGAACinsTTCTGGGGCT​(p.Gln505LeufsTer51) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NPRL3 NM_001077350.3 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.76
• Publications: 0 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: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.115 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-88724-GTTCT-AGCCCCAGAA is Pathogenic according to our data. Variant chr16-88724-GTTCT-AGCCCCAGAA is described in ClinVar as Pathogenic. ClinVar VariationId is 542797.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPRL3	NM_001077350.3	MANE Select	c.1514_1518delAGAACinsTTCTGGGGCT	p.Gln505LeufsTer51	frameshift missense	Exon 13 of 14	NP_001070818.1
	NPRL3	NM_001243248.2		c.1439_1443delAGAACinsTTCTGGGGCT	p.Gln480LeufsTer51	frameshift missense	Exon 12 of 13	NP_001230177.1
	NPRL3	NM_001243249.2		c.1439_1443delAGAACinsTTCTGGGGCT	p.Gln480LeufsTer51	frameshift missense	Exon 11 of 12	NP_001230178.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPRL3	ENST00000611875.5	TSL:5 MANE Select	c.1514_1518delAGAACinsTTCTGGGGCT	p.Gln505LeufsTer51	frameshift missense	Exon 13 of 14	ENSP00000478273.1
	NPRL3	ENST00000399953.7	TSL:1	c.1439_1443delAGAACinsTTCTGGGGCT	p.Gln480LeufsTer51	frameshift missense	Exon 11 of 12	ENSP00000382834.4
	NPRL3	ENST00000621703.4	TSL:1	n.*1099_*1103delAGAACinsTTCTGGGGCT		non_coding_transcript_exon	Exon 10 of 11	ENSP00000477801.1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Epilepsy, familial focal, with variable foci 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555439541; hg19: chr16-138723;