rs886037959

Variant names:

• chr16-88891-CTGT-GGATGGGTCA
• rs886037959
• NM_001077350.3:c.1352-4_1352-1delACAGinsTGACCCATCC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001077350.3(NPRL3):​c.1352-4_1352-1delACAGinsTGACCCATCC variant causes a splice acceptor, splice region, intron 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 (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NPRL3 NM_001077350.3 splice_acceptor, splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial focal epilepsy with variable foci

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.8, offset of 4, new splice context is: tccccctgacccatccccAGcag. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-88891-CTGT-GGATGGGTCA is Pathogenic according to our data. Variant chr16-88891-CTGT-GGATGGGTCA is described in ClinVar as Pathogenic. ClinVar VariationId is 254358.Status of the report is no_assertion_criteria_provided, 0 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPRL3	NM_001077350.3	MANE Select	c.1352-4_1352-1delACAGinsTGACCCATCC		splice_acceptor splice_region intron	N/A	NP_001070818.1	Q12980
	NPRL3	NM_001243248.2		c.1277-4_1277-1delACAGinsTGACCCATCC		splice_acceptor splice_region intron	N/A	NP_001230177.1	B7Z6Q0
	NPRL3	NM_001243249.2		c.1277-4_1277-1delACAGinsTGACCCATCC		splice_acceptor splice_region intron	N/A	NP_001230178.1	B7Z6Q0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPRL3	ENST00000611875.5	TSL:5 MANE Select	c.1352-4_1352-1delACAGinsTGACCCATCC		splice_acceptor splice_region intron	N/A	ENSP00000478273.1	Q12980
	NPRL3	ENST00000399953.7	TSL:1	c.1277-4_1277-1delACAGinsTGACCCATCC		splice_acceptor splice_region intron	N/A	ENSP00000382834.4	B7Z6Q0
	NPRL3	ENST00000621703.4	TSL:1	n.*937-4_*937-1delACAGinsTGACCCATCC		splice_acceptor splice_region intron	N/A	ENSP00000477801.1	A0A087WTE2

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

Significance: Pathogenic

Revision: no assertion criteria provided

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
Mutation Taster		=10/90	disease causing

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs886037959;

hg19: chr16-138889;