rs1555441032

Positions:

• chr16-98145-C-CTG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001077350.3(NPRL3):​c.923_924insCA​(p.Gln308HisfsTer106) variant causes a frameshift, splice region 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPRL3 NM_001077350.3 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.67

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-98145-C-CTG is Pathogenic according to our data. Variant chr16-98145-C-CTG is described in ClinVar as [Pathogenic]. Clinvar id is 542798.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPRL3	NM_001077350.3	c.923_924insCA	p.Gln308HisfsTer106	frameshift_variant, splice_region_variant	9/14	ENST00000611875.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPRL3	ENST00000611875.5	c.923_924insCA	p.Gln308HisfsTer106	frameshift_variant, splice_region_variant	9/14	5	NM_001077350.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2020

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with NPRL3-related conditions. ClinVar contains an entry for this variant (Variation ID: 542798). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln308Hisfs*106) in the NPRL3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPRL3 are known to be pathogenic (PMID: 26285051, 26505888). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555441032; hg19: chr16-148143;