NM_001077350.3:c.1589T>A

Variant names:

• chr16-86826-A-T
• rs1453118437
• NM_001077350.3:c.1589T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001077350.3(NPRL3):​c.1589T>A​(p.Met530Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M530I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: NPRL3 NM_001077350.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.21
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPRL3	NM_001077350.3	c.1589T>A	p.Met530Lys	missense_variant	Exon 14 of 14	ENST00000611875.5	NP_001070818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPRL3	ENST00000611875.5	c.1589T>A	p.Met530Lys	missense_variant	Exon 14 of 14	5	NM_001077350.3	ENSP00000478273.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D;.;D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D;D;.
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Benign	-0.73	T
PhyloP100		9.2
PrimateAI	Pathogenic	0.79	T
REVEL	Pathogenic	0.81
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.93	P;.;P
Vest4		0.95
MutPred		0.74		Gain of ubiquitination at M530 (P = 0.023);.;Gain of ubiquitination at M530 (P = 0.023);
MVP		0.57
MPC		1.0
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.74
gMVP		0.96

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

Other links and lift over

dbSNP: rs1453118437; hg19: chr16-136825;