chr16-112635-G-A

Variant names:

• chr16-112635-G-A
• rs140092767
• NM_001077350.3:c.534C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001039476.3(NPRL3):​c.-4C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000697 in 1,589,352 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (2 hom.)
• Consequence: NPRL3 NM_001039476.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.348
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 16-112635-G-A is Benign according to our data. Variant chr16-112635-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 476224.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 = 0.00389 (593/152314) while in subpopulation AFR AF = 0.0137 (568/41586). AF 95% confidence interval is 0.0127. There are 5 homozygotes in GnomAd4. There are 272 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 593 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039476.3. 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.534C>T	p.Ser178Ser	synonymous	Exon 6 of 14	NP_001070818.1	Q12980
	NPRL3	NM_001039476.3		c.-4C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 11	NP_001034565.1
	NPRL3	NM_001243248.2		c.459C>T	p.Ser153Ser	synonymous	Exon 5 of 13	NP_001230177.1	B7Z6Q0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPRL3	ENST00000611875.5	TSL:5 MANE Select	c.534C>T	p.Ser178Ser	synonymous	Exon 6 of 14	ENSP00000478273.1	Q12980
	NPRL3	ENST00000399953.7	TSL:1	c.459C>T	p.Ser153Ser	synonymous	Exon 4 of 12	ENSP00000382834.4	B7Z6Q0
	NPRL3	ENST00000621703.4	TSL:1	n.*119C>T		non_coding_transcript_exon	Exon 3 of 11	ENSP00000477801.1	A0A087WTE2

Frequencies

GnomAD3 genomes AF: 0.00388 AC: 591 AN: 152196 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000852 AC: 191 AN: 224094 AF XY: 0.000585

Gnomad AFR exome AF: 0.0124

Gnomad AMR exome AF: 0.000554

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000696

Gnomad OTH exome AF: 0.000181

GnomAD4 exome AF: 0.000358 AC: 515 AN: 1437038 Hom.: 2 Cov.: 31 AF XY: 0.000298 AC XY: 212 AN XY: 711658

African (AFR) AF: 0.0124 AC: 407 AN: 32906

American (AMR) AF: 0.000767 AC: 33 AN: 43038

Ashkenazi Jewish (ASJ) AF: 0.0000396 AC: 1 AN: 25242

East Asian (EAS) AF: 0.00 AC: 0 AN: 38666

South Asian (SAS) AF: 0.0000484 AC: 4 AN: 82704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51690

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.0000273 AC: 30 AN: 1097754

Other (OTH) AF: 0.000674 AC: 40 AN: 59332

GnomAD4 genome AF: 0.00389 AC: 593 AN: 152314 Hom.: 5 Cov.: 33 AF XY: 0.00365 AC XY: 272 AN XY: 74482

African (AFR) AF: 0.0137 AC: 568 AN: 41586

American (AMR) AF: 0.000915 AC: 14 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68018

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00228 Hom.: 3

Bravo AF: 0.00453

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Epilepsy, familial focal, with variable foci 3 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	5.6
DANN	Benign	0.67
PhyloP100		-0.35
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=277/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs140092767; hg19: chr16-162634;