Genetic Variant NM_020761.3:c.1518A>G (chr17-80880423-A-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_020761.3(RPTOR):c.1518A>G(p.Gln506Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,612,836 control chromosomes in the GnomAD database, including 54,709 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.23 ( 4096 hom., cov: 32)

Exomes 𝑓: 0.26 ( 50613 hom. )

Consequence

RPTOR
NM_020761.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.857

Publications

28 publications found

Variant links:

Genes affected

RPTOR (HGNC:30287): (regulatory associated protein of MTOR complex 1) This gene encodes a component of a signaling pathway that regulates cell growth in response to nutrient and insulin levels. The encoded protein forms a stoichiometric complex with the mTOR kinase, and also associates with eukaryotic initiation factor 4E-binding protein-1 and ribosomal protein S6 kinase. The protein positively regulates the downstream effector ribosomal protein S6 kinase, and negatively regulates the mTOR kinase. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

RPTOR links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP7

Synonymous conserved (PhyloP=-0.857 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPTOR	NM_020761.3 link	c.1518A>G	p.Gln506Gln	synonymous_variant	Exon 14 of 34	ENST00000306801.8	NP_065812.1	Q8N122-1Q6DKI0
RPTOR	NM_001163034.2 link	c.1510-11297A>G		intron_variant	Intron 13 of 29		NP_001156506.1	Q8N122-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPTOR	ENST00000306801.8 link	c.1518A>G	p.Gln506Gln	synonymous_variant	Exon 14 of 34	1	NM_020761.3	ENSP00000307272.3		Q8N122-1

Frequencies

GnomAD3 genomes

AF:

0.226

AC:

34373

AN:

152032

Hom.:

4092

Cov.:

show subpopulations

Gnomad AFR

AF:

0.143

Gnomad AMI

AF:

0.207

Gnomad AMR

AF:

0.253

Gnomad ASJ

AF:

0.247

Gnomad EAS

AF:

0.371

Gnomad SAS

AF:

0.283

Gnomad FIN

AF:

0.206

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.258

Gnomad OTH

AF:

0.241

GnomAD2 exomes

AF:

0.258

AC:

64765

AN:

251220

AF XY:

0.259

show subpopulations

Gnomad AFR exome

AF:

0.138

Gnomad AMR exome

AF:

0.269

Gnomad ASJ exome

AF:

0.254

Gnomad EAS exome

AF:

0.383

Gnomad FIN exome

AF:

0.208

Gnomad NFE exome

AF:

0.260

Gnomad OTH exome

AF:

0.257

GnomAD4 exome

AF:

0.260

AC:

380484

AN:

1460686

Hom.:

50613

Cov.:

AF XY:

0.261

AC XY:

189433

AN XY:

726686

show subpopulations

African (AFR)

AF:

0.136

AC:

4567

AN:

33472

American (AMR)

AF:

0.265

AC:

11847

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.253

AC:

6619

AN:

26130

East Asian (EAS)

AF:

0.367

AC:

14549

AN:

39680

South Asian (SAS)

AF:

0.266

AC:

22920

AN:

86242

European-Finnish (FIN)

AF:

0.210

AC:

11154

AN:

53054

Middle Eastern (MID)

AF:

0.241

AC:

1387

AN:

5764

European-Non Finnish (NFE)

AF:

0.263

AC:

291804

AN:

1111282

Other (OTH)

AF:

0.259

AC:

15637

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

13173

26346

39519

52692

65865

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9890

19780

29670

39560

49450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.226

AC:

34392

AN:

152150

Hom.:

4096

Cov.:

AF XY:

0.226

AC XY:

16845

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.143

AC:

5918

AN:

41510

American (AMR)

AF:

0.253

AC:

3872

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.247

AC:

856

AN:

3466

East Asian (EAS)

AF:

0.371

AC:

1909

AN:

5152

South Asian (SAS)

AF:

0.284

AC:

1367

AN:

4814

European-Finnish (FIN)

AF:

0.206

AC:

2186

AN:

10612

Middle Eastern (MID)

AF:

0.184

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.258

AC:

17534

AN:

67990

Other (OTH)

AF:

0.241

AC:

507

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1352

2704

4057

5409

6761

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

372

744

1116

1488

1860

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.250

Hom.:

7697

Bravo

AF:

0.225

Asia WGS

AF:

0.310

AC:

1077

AN:

3478

EpiCase

AF:

0.264

EpiControl

AF:

0.266

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.28

(source)

DANN

Benign

0.56

PhyloP100

-0.86

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over