17-80883477-C-T

Variant names:

• chr17-80883477-C-T
• rs548409186
• NM_020761.3:c.1643C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_020761.3(RPTOR):​c.1643C>T​(p.Thr548Met) variant causes a missense change. The variant allele was found at a frequency of 0.000026 in 1,614,038 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T548T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: RPTOR NM_020761.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.14
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3099826).
• BS2: High AC in GnomAd4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020761.3. 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
	RPTOR	NM_020761.3	MANE Select	c.1643C>T	p.Thr548Met	missense	Exon 15 of 34	NP_065812.1	Q8N122-1
	RPTOR	NM_001163034.2		c.1510-8243C>T		intron	N/A	NP_001156506.1	Q8N122-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPTOR	ENST00000306801.8	TSL:1 MANE Select	c.1643C>T	p.Thr548Met	missense	Exon 15 of 34	ENSP00000307272.3	Q8N122-1
	RPTOR	ENST00000575542.5	TSL:1	n.1130C>T		non_coding_transcript_exon	Exon 11 of 30
	RPTOR	ENST00000697423.1		c.1697C>T	p.Thr566Met	missense	Exon 15 of 34	ENSP00000513305.1	A0A8V8TMD9

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000517 AC: 13 AN: 251426 AF XY: 0.0000662

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461714 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 727168

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

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

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111938

Other (OTH) AF: 0.0000497 AC: 3 AN: 60390

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74474

African (AFR) AF: 0.0000241 AC: 1 AN: 41578

American (AMR) AF: 0.00 AC: 0 AN: 15302

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

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5176

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.26	N
PhyloP100		7.1
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.20
Sift	Benign	0.11	T
Sift4G	Benign	0.15	T
Polyphen		0.99	D
Vest4		0.73
MutPred		0.34		Loss of catalytic residue at T548 (P = 0.0173)
MVP		0.38
MPC		1.9
ClinPred		0.27	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.35
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs548409186; hg19: chr17-78857277;