rs1555441032

Variant names:

• chr16-98145-C-CTG
• rs1555441032
• NM_001077350.3:c.922_923dupCA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001077350.3(NPRL3):​c.922_923dupCA​(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
• 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 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 VariationId is 542798.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPRL3	NM_001077350.3	MANE Select	c.922_923dupCA	p.Gln308HisfsTer106	frameshift splice_region	Exon 9 of 14	NP_001070818.1	Q12980
	NPRL3	NM_001243248.2		c.847_848dupCA	p.Gln283HisfsTer106	frameshift splice_region	Exon 8 of 13	NP_001230177.1	B7Z6Q0
	NPRL3	NM_001243249.2		c.847_848dupCA	p.Gln283HisfsTer106	frameshift splice_region	Exon 7 of 12	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.922_923dupCA	p.Gln308HisfsTer106	frameshift splice_region	Exon 9 of 14	ENSP00000478273.1	Q12980
	NPRL3	ENST00000399953.7	TSL:1	c.847_848dupCA	p.Gln283HisfsTer106	frameshift splice_region	Exon 7 of 12	ENSP00000382834.4	B7Z6Q0
	NPRL3	ENST00000621703.4	TSL:1	n.*507_*508dupCA		splice_region non_coding_transcript_exon	Exon 6 of 11	ENSP00000477801.1	A0A087WTE2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

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		7.7
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1555441032; hg19: chr16-148143;