16-110604-T-G

Position:

• chr16-110604-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001077350.3(NPRL3):​c.550A>C​(p.Asn184His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00671 in 1,607,092 control chromosomes in the GnomAD database, including 145 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (102 hom.)
• Consequence: NPRL3 NM_001077350.3 missense, splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.04

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032077432).
• BP6: Variant 16-110604-T-G is Benign according to our data. Variant chr16-110604-T-G is described in ClinVar as [Benign]. Clinvar id is 476225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.015 (2286/152270) while in subpopulation AFR AF= 0.0334 (1389/41556). AF 95% confidence interval is 0.032. There are 43 homozygotes in gnomad4. There are 1202 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2286 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPRL3	NM_001077350.3	c.550A>C	p.Asn184His	missense_variant, splice_region_variant	7/14	ENST00000611875.5	NP_001070818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPRL3	ENST00000611875.5	c.550A>C	p.Asn184His	missense_variant, splice_region_variant	7/14	5	NM_001077350.3	ENSP00000478273	P1

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2276 AN: 152152 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.0333

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00668

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.0126

Gnomad FIN AF: 0.0372

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00395

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00927 AC: 2203 AN: 237606 Hom.: 26 AF XY: 0.00912 AC XY: 1173 AN XY: 128614

Gnomad AFR exome AF: 0.0317

Gnomad AMR exome AF: 0.00421

Gnomad ASJ exome AF: 0.00133

Gnomad EAS exome AF: 0.000459

Gnomad SAS exome AF: 0.0147

Gnomad FIN exome AF: 0.0308

Gnomad NFE exome AF: 0.00454

Gnomad OTH exome AF: 0.00646

GnomAD4 exome AF: 0.00584 AC: 8502 AN: 1454822 Hom.: 102 Cov.: 30 AF XY: 0.00613 AC XY: 4430 AN XY: 723038

Gnomad4 AFR exome AF: 0.0369

Gnomad4 AMR exome AF: 0.00402

Gnomad4 ASJ exome AF: 0.00150

Gnomad4 EAS exome AF: 0.000328

Gnomad4 SAS exome AF: 0.0147

Gnomad4 FIN exome AF: 0.0303

Gnomad4 NFE exome AF: 0.00328

Gnomad4 OTH exome AF: 0.00830

GnomAD4 genome AF: 0.0150 AC: 2286 AN: 152270 Hom.: 43 Cov.: 32 AF XY: 0.0161 AC XY: 1202 AN XY: 74468

Gnomad4 AFR AF: 0.0334

Gnomad4 AMR AF: 0.00667

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00271

Gnomad4 SAS AF: 0.0126

Gnomad4 FIN AF: 0.0372

Gnomad4 NFE AF: 0.00395

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.00733 Hom.: 6

Bravo AF: 0.0130

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.0262 AC: 105

ESP6500EA AF: 0.00289 AC: 24

ExAC AF: 0.00963 AC: 1164

Asia WGS AF: 0.0220 AC: 78 AN: 3478

ClinVar

Significance: 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	Sep 14, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Benign	0.093	T;.;T;.
Eigen	Benign	-0.038
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.84	T;T;.;T
MetaRNN	Benign	0.0032	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.38	T
REVEL	Benign	0.051
Sift4G	Benign	0.43	T;T;T;.
Polyphen		0.51	P;B;P;.
Vest4		0.15
MVP		0.18
MPC		0.26
ClinPred		0.0049	T
GERP RS		0.58
Varity_R		0.079
gMVP		0.22

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: rs73478320; hg19: chr16-160602;