rs1060501911

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_004958.4(MTOR):​c.7370T>C​(p.Ile2457Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

MTOR
NM_004958.4 missense

Scores

1
1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.63
Variant links:
Genes affected
MTOR (HGNC:3942): (mechanistic target of rapamycin kinase) The protein encoded by this gene belongs to a family of phosphatidylinositol kinase-related kinases. These kinases mediate cellular responses to stresses such as DNA damage and nutrient deprivation. This kinase is a component of two distinct complexes, mTORC1, which controls protein synthesis, cell growth and proliferation, and mTORC2, which is a regulator of the actin cytoskeleton, and promotes cell survival and cell cycle progression. This protein acts as the target for the cell-cycle arrest and immunosuppressive effects of the FKBP12-rapamycin complex. Inhibitors of mTOR are used in organ transplants as immunosuppressants, and are being evaluated for their therapeutic potential in SARS-CoV-2 infections. Mutations in this gene are associated with Smith-Kingsmore syndrome and somatic focal cortical dysplasia type II. The ANGPTL7 gene is located in an intron of this gene. [provided by RefSeq, Aug 2020]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MTOR. . Gene score misZ 7.0206 (greater than the threshold 3.09). Trascript score misZ 9.4864 (greater than threshold 3.09). GenCC has associacion of gene with macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes.
BP4
Computational evidence support a benign effect (MetaRNN=0.18021214).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MTORNM_004958.4 linkuse as main transcriptc.7370T>C p.Ile2457Thr missense_variant 55/58 ENST00000361445.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MTORENST00000361445.9 linkuse as main transcriptc.7370T>C p.Ile2457Thr missense_variant 55/581 NM_004958.4 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 29, 2016This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MTOR-related disease. This sequence change replaces isoleucine with threonine at codon 2457 of the MTOR protein (p.Ile2457Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
22
DANN
Benign
0.96
DEOGEN2
Benign
0.25
T;T;.
Eigen
Benign
-0.074
Eigen_PC
Benign
0.15
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.83
T;T;T
M_CAP
Benign
0.0037
T
MetaRNN
Benign
0.18
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.33
.;N;.
MutationTaster
Benign
0.97
D;D
PrimateAI
Pathogenic
0.80
T
PROVEAN
Benign
-0.77
N;N;N
REVEL
Benign
0.090
Sift
Benign
0.59
T;T;T
Sift4G
Benign
0.40
T;T;T
Polyphen
0.0
.;B;.
Vest4
0.15
MutPred
0.60
.;Loss of stability (P = 0.0023);.;
MVP
0.28
MPC
1.6
ClinPred
0.67
D
GERP RS
5.8
Varity_R
0.092
gMVP
0.51

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1060501911; hg19: chr1-11169783; API