Genetic Variant NM_004958.4:c.5170A>T (chr1-11134427-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004958.4(MTOR):c.5170A>T(p.Met1724Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1724T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

MTOR
NM_004958.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.31

Publications

0 publications found

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]

MTOR Gene-Disease associations (from GenCC):

macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Illumina
overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

MTOR links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12866837).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004958.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTOR	NM_004958.4	MANE Select	c.5170A>T	p.Met1724Leu	missense	Exon 37 of 58	NP_004949.1	P42345
MTOR	NM_001386500.1		c.5170A>T	p.Met1724Leu	missense	Exon 37 of 58	NP_001373429.1	P42345
MTOR	NM_001386501.1		c.3922A>T	p.Met1308Leu	missense	Exon 36 of 57	NP_001373430.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTOR	ENST00000361445.9	TSL:1 MANE Select	c.5170A>T	p.Met1724Leu	missense	Exon 37 of 58	ENSP00000354558.4	P42345
MTOR	ENST00000934315.1		c.5224A>T	p.Met1742Leu	missense	Exon 37 of 58	ENSP00000604374.1
MTOR	ENST00000934312.1		c.5191A>T	p.Met1731Leu	missense	Exon 37 of 58	ENSP00000604371.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.26

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.0052

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.2

PhyloP100

1.3

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.10

REVEL

Benign

0.13

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0030

Vest4

0.43

MutPred

0.54

Loss of disorder (P = 0.0588)

MVP

0.55

MPC

0.75

ClinPred

0.29

GERP RS

-0.047

Varity_R

0.14

gMVP

0.31

Mutation Taster

=79/21

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over