rs577354419

Variant names:

• chr16-86520-C-T
• rs577354419
• NM_001077350.3:c.*185G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001077350.3(NPRL3):​c.*185G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00377 in 609,340 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0033 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0039 (8 hom.)
• Consequence: NPRL3 NM_001077350.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.29
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-86520-C-T is Benign according to our data. Variant chr16-86520-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1195638.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00328 (499/152332) while in subpopulation NFE AF = 0.00444 (302/68010). AF 95% confidence interval is 0.00403. There are 2 homozygotes in GnomAd4. There are 271 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 499 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.*185G>A		3_prime_UTR	Exon 14 of 14	NP_001070818.1	Q12980
	NPRL3	NM_001243248.2		c.*185G>A		3_prime_UTR	Exon 13 of 13	NP_001230177.1	B7Z6Q0
	NPRL3	NM_001243249.2		c.*185G>A		3_prime_UTR	Exon 12 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.*185G>A		3_prime_UTR	Exon 14 of 14	ENSP00000478273.1	Q12980
	NPRL3	ENST00000399953.7	TSL:1	c.*185G>A		3_prime_UTR	Exon 12 of 12	ENSP00000382834.4	B7Z6Q0
	NPRL3	ENST00000621703.4	TSL:1	n.*1480G>A		non_coding_transcript_exon	Exon 11 of 11	ENSP00000477801.1	A0A087WTE2

Frequencies

GnomAD3 genomes AF: 0.00328 AC: 499 AN: 152214 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00443

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00394 AC: 1799 AN: 457008 Hom.: 8 Cov.: 5 AF XY: 0.00365 AC XY: 869 AN XY: 238230

African (AFR) AF: 0.00111 AC: 14 AN: 12632

American (AMR) AF: 0.000716 AC: 13 AN: 18168

Ashkenazi Jewish (ASJ) AF: 0.000972 AC: 13 AN: 13372

East Asian (EAS) AF: 0.00 AC: 0 AN: 30528

South Asian (SAS) AF: 0.00133 AC: 58 AN: 43472

European-Finnish (FIN) AF: 0.0120 AC: 341 AN: 28506

Middle Eastern (MID) AF: 0.00104 AC: 2 AN: 1932

European-Non Finnish (NFE) AF: 0.00450 AC: 1272 AN: 282512

Other (OTH) AF: 0.00332 AC: 86 AN: 25886

GnomAD4 genome AF: 0.00328 AC: 499 AN: 152332 Hom.: 2 Cov.: 34 AF XY: 0.00364 AC XY: 271 AN XY: 74480

African (AFR) AF: 0.000793 AC: 33 AN: 41588

American (AMR) AF: 0.000849 AC: 13 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4826

European-Finnish (FIN) AF: 0.0123 AC: 131 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00444 AC: 302 AN: 68010

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00360 Hom.: 0

Bravo AF: 0.00248

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.2
DANN	Benign	0.62
PhyloP100		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs577354419; hg19: chr16-136519;