16-92644-C-T

Variant names:

• chr16-92644-C-T
• rs148130584
• NM_001077350.3:c.1113G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001077350.3(NPRL3):​c.1113G>A​(p.Pro371Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,461,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P371P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: NPRL3 NM_001077350.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.04
• 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 16-92644-C-T is Benign according to our data. Variant chr16-92644-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 582619.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-4.03 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 26 AD gene.

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.1113G>A	p.Pro371Pro	synonymous	Exon 11 of 14	NP_001070818.1	Q12980
	NPRL3	NM_001243248.2		c.1038G>A	p.Pro346Pro	synonymous	Exon 10 of 13	NP_001230177.1	B7Z6Q0
	NPRL3	NM_001243249.2		c.1038G>A	p.Pro346Pro	synonymous	Exon 9 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.1113G>A	p.Pro371Pro	synonymous	Exon 11 of 14	ENSP00000478273.1	Q12980
	NPRL3	ENST00000399953.7	TSL:1	c.1038G>A	p.Pro346Pro	synonymous	Exon 9 of 12	ENSP00000382834.4	B7Z6Q0
	NPRL3	ENST00000621703.4	TSL:1	n.*698G>A		non_coding_transcript_exon	Exon 8 of 11	ENSP00000477801.1	A0A087WTE2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 248370 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461412 Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17 AN XY: 726962

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000448 AC: 2 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111746

Other (OTH) AF: 0.0000663 AC: 4 AN: 60360

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely benign

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
BayesDel_noAF	Benign	-0.61
CADD	Benign	2.1
DANN	Benign	0.68
PhyloP100		-4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs148130584; hg19: chr16-142642;