rs764156867

Variant names:

• chr16-138151-T-C
• rs764156867
• NM_001077350.3:c.117A>G

Your query was ambiguous. Multiple possible variants found:

• chr16-138151-T-C
• chr16-138151-T-G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001077350.3(NPRL3):​c.117A>G​(p.Thr39Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,598,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NPRL3 NM_001077350.3 splice_region, synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.412
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP7: Synonymous conserved (PhyloP=0.412 with no splicing effect.

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.117A>G	p.Thr39Thr	splice_region synonymous	Exon 2 of 14	NP_001070818.1	Q12980
	NPRL3	NM_001243247.2		c.-255A>G		splice_region	Exon 2 of 15	NP_001230176.1
	NPRL3	NM_001039476.3		c.-216A>G		splice_region	Exon 1 of 11	NP_001034565.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPRL3	ENST00000611875.5	TSL:5 MANE Select	c.117A>G	p.Thr39Thr	splice_region synonymous	Exon 2 of 14	ENSP00000478273.1	Q12980
	NPRL3	ENST00000399953.7	TSL:1	c.117A>G	p.Thr39Thr	splice_region synonymous	Exon 1 of 12	ENSP00000382834.4	B7Z6Q0
	NPRL3	ENST00000621703.4	TSL:1	n.117A>G		splice_region non_coding_transcript_exon	Exon 1 of 11	ENSP00000477801.1	A0A087WTE2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152006 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000451 AC: 1 AN: 221572 AF XY: 0.00000827

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000102

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1446828 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718330

African (AFR) AF: 0.00 AC: 0 AN: 33080

American (AMR) AF: 0.00 AC: 0 AN: 43002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25738

East Asian (EAS) AF: 0.00 AC: 0 AN: 38926

South Asian (SAS) AF: 0.00 AC: 0 AN: 83380

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51766

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1105340

Other (OTH) AF: 0.00 AC: 0 AN: 59838

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152006 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74236

African (AFR) AF: 0.0000242 AC: 1 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	-0.51
CADD	Benign	14
DANN	Benign	0.81
PhyloP100		0.41
PromoterAI		0.0087	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs764156867; hg19: chr16-188150;