rs886037962

chr16-92686-TG-T

Variant summary

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

The NM_001077350.3(NPRL3):c.1070del(p.Pro357HisfsTer56) variant causes a frameshift 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
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.75

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 16-92686-TG-T is Pathogenic according to our data. Variant chr16-92686-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 254361.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.1070del	p.Pro357HisfsTer56	frameshift_variant	11/14	ENST00000611875.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPRL3	ENST00000611875.5	c.1070del	p.Pro357HisfsTer56	frameshift_variant	11/14	5	NM_001077350.3	P1
NPRL3	ENST00000399953.7	c.995del	p.Pro332HisfsTer56	frameshift_variant	9/12	1
NPRL3	ENST00000621703.4	c.*655del		3_prime_UTR_variant, NMD_transcript_variant	8/11	1
NPRL3	ENST00000622194.4	c.*706del		3_prime_UTR_variant, NMD_transcript_variant	9/12	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Epilepsy, familial focal, with variable foci 3 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	This sequence change creates a premature translational stop signal (p.Pro357Hisfs*56) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial focal epilepsy with variable foci (PMID: 27173016). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 254361). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 21, 2016	- -

Computational scores

Source: dbNSFP v4.3

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: rs886037962; hg19: chr16-142684;