Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004958.4(MTOR):c.3462G>C(p.Arg1154Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00738 in 1,614,122 control chromosomes in the GnomAD database, including 412 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R1154R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.011 ( 68 hom., cov: 32)

Exomes 𝑓: 0.0070 ( 344 hom. )

Consequence

MTOR
NM_004958.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.223

Publications

9 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: Illumina, Orphanet, Labcorp Genetics (formerly Invitae), G2P
overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

MTOR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 1-11212411-C-G is Benign according to our data. Variant chr1-11212411-C-G is described in ClinVar as Benign. ClinVar VariationId is 414901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.223 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0612 is higher than 0.05.

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
MTOR	NM_004958.4	MANE Select	c.3462G>C	p.Arg1154Arg	synonymous	Exon 23 of 58	NP_004949.1
MTOR	NM_001386500.1		c.3462G>C	p.Arg1154Arg	synonymous	Exon 23 of 58	NP_001373429.1
MTOR	NM_001386501.1		c.2214G>C	p.Arg738Arg	synonymous	Exon 22 of 57	NP_001373430.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MTOR	ENST00000361445.9	TSL:1 MANE Select	c.3462G>C	p.Arg1154Arg	synonymous	Exon 23 of 58	ENSP00000354558.4
MTOR	ENST00000703143.2		c.3462G>C	p.Arg1154Arg	synonymous	Exon 23 of 58	ENSP00000515200.2
MTOR	ENST00000703140.1		c.3249G>C	p.Arg1083Arg	synonymous	Exon 21 of 56	ENSP00000515197.1

Frequencies

GnomAD3 genomes

AF:

0.0112

AC:

1706

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00316

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0645

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0449

Gnomad SAS

AF:

0.0655

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.0198

AC:

4976

AN:

251248

AF XY:

0.0200

show subpopulations

Gnomad AFR exome

AF:

0.00295

Gnomad AMR exome

AF:

0.0641

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0411

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000211

Gnomad OTH exome

AF:

0.0153

GnomAD4 exome

AF:

0.00698

AC:

10208

AN:

1461850

Hom.:

344

Cov.:

AF XY:

0.00832

AC XY:

6050

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00311

AC:

104

AN:

33478

American (AMR)

AF:

0.0624

AC:

2790

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0375

AC:

1489

AN:

39698

South Asian (SAS)

AF:

0.0581

AC:

5014

AN:

86254

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00329

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000156

AC:

174

AN:

1112000

Other (OTH)

AF:

0.0102

AC:

617

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

504

1009

1513

2018

2522

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

142

284

426

568

710

<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:

0.0112

AC:

1708

AN:

152272

Hom.:

Cov.:

AF XY:

0.0140

AC XY:

1041

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00322

AC:

134

AN:

41570

American (AMR)

AF:

0.0645

AC:

986

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.0450

AC:

232

AN:

5160

South Asian (SAS)

AF:

0.0649

AC:

313

AN:

4822

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68022

Other (OTH)

AF:

0.00992

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

137

206

274

343

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00192

Hom.:

Bravo

AF:

0.0132

EpiCase

AF:

0.000382

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

8.7

(source)

DANN

Benign

0.70

PhyloP100

-0.22

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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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NM_004958.4:c.3462G>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over