rs202015937

Positions:

• chr16-88726-T-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BS1 BS2

The NM_001077350.3(NPRL3):​c.1516A>T​(p.Asn506Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,613,032 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (1 hom.)
• Consequence: NPRL3 NM_001077350.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.76

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.35745215).
• BP6: Variant 16-88726-T-A is Benign according to our data. Variant chr16-88726-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 542804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88726-T-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000815 (124/152194) while in subpopulation NFE AF= 0.00148 (101/68040). AF 95% confidence interval is 0.00125. There are 0 homozygotes in gnomad4. There are 49 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 124 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPRL3	NM_001077350.3	c.1516A>T	p.Asn506Tyr	missense_variant	13/14	ENST00000611875.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPRL3	ENST00000611875.5	c.1516A>T	p.Asn506Tyr	missense_variant	13/14	5	NM_001077350.3	P1

Frequencies

GnomAD3 genomes AF: 0.000815 AC: 124 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00148

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.000715 AC: 177 AN: 247476 Hom.: 1 AF XY: 0.000647 AC XY: 87 AN XY: 134496

Gnomad AFR exome AF: 0.000327

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000932

Gnomad NFE exome AF: 0.00146

Gnomad OTH exome AF: 0.000499

GnomAD4 exome AF: 0.00144 AC: 2099 AN: 1460838 Hom.: 1 Cov.: 31 AF XY: 0.00139 AC XY: 1007 AN XY: 726578

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.00184

Gnomad4 OTH exome AF: 0.000481

GnomAD4 genome AF: 0.000815 AC: 124 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.000659 AC XY: 49 AN XY: 74344

Gnomad4 AFR AF: 0.000386

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00148

Gnomad4 OTH AF: 0.000959

Alfa AF: 0.00134 Hom.: 0

Bravo AF: 0.000816

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000230 AC: 1

ESP6500EA AF: 0.00199 AC: 17

ExAC AF: 0.000635 AC: 77

EpiCase AF: 0.00120

EpiControl AF: 0.00154

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 30, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	NPRL3: BS1 -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;.;T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D;.
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Uncertain	-0.12	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
Sift4G	Uncertain	0.053	T;T;T
Polyphen		0.99	D;.;D
Vest4		0.89
MVP		0.57
MPC		0.89
ClinPred		0.39	T
GERP RS		5.5
Varity_R		0.40
gMVP		0.80

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: rs202015937; hg19: chr16-138725; COSMIC: COSV54739631; COSMIC: COSV54739631;