dbSNP rs56051835: MTOR:p.Leu2208Leu (chr1-11124536-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004958.4(MTOR):c.6624T>C(p.Leu2208Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00296 in 1,611,314 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 56 hom. )

Consequence

MTOR
NM_004958.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.198

Publications

7 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:

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=-0.6).

BP6

Variant 1-11124536-A-G is Benign according to our data. Variant chr1-11124536-A-G is described in ClinVar as Benign. ClinVar VariationId is 414895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.198 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00303 (462/152326) while in subpopulation SAS AF = 0.0149 (72/4818). AF 95% confidence interval is 0.0122. There are 9 homozygotes in GnomAd4. There are 248 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 462 AD gene.

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.6624T>C	p.Leu2208Leu	synonymous	Exon 47 of 58	NP_004949.1	P42345
MTOR	NM_001386500.1		c.6624T>C	p.Leu2208Leu	synonymous	Exon 47 of 58	NP_001373429.1	P42345
MTOR	NM_001386501.1		c.5376T>C	p.Leu1792Leu	synonymous	Exon 46 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.6624T>C	p.Leu2208Leu	synonymous	Exon 47 of 58	ENSP00000354558.4	P42345
MTOR	ENST00000934315.1		c.6678T>C	p.Leu2226Leu	synonymous	Exon 47 of 58	ENSP00000604374.1
MTOR	ENST00000934312.1		c.6645T>C	p.Leu2215Leu	synonymous	Exon 47 of 58	ENSP00000604371.1

Frequencies

GnomAD3 genomes

AF:

0.00304

AC:

463

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.0446

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0149

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00212

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00499

AC:

1256

AN:

251458

AF XY:

0.00551

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00150

Gnomad ASJ exome

AF:

0.0444

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00302

Gnomad OTH exome

AF:

0.00554

GnomAD4 exome

AF:

0.00295

AC:

4309

AN:

1458988

Hom.:

Cov.:

AF XY:

0.00335

AC XY:

2432

AN XY:

725052

show subpopulations

African (AFR)

AF:

0.000478

AC:

AN:

33462

American (AMR)

AF:

0.00161

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.0440

AC:

1150

AN:

26114

East Asian (EAS)

AF:

0.0000757

AC:

AN:

39628

South Asian (SAS)

AF:

0.0126

AC:

1089

AN:

86198

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.0101

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00142

AC:

1579

AN:

1109494

Other (OTH)

AF:

0.00554

AC:

334

AN:

60246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

219

437

656

874

1093

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.00303

AC:

462

AN:

152326

Hom.:

Cov.:

AF XY:

0.00333

AC XY:

248

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41560

American (AMR)

AF:

0.00255

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0446

AC:

155

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.0149

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00212

AC:

144

AN:

68040

Other (OTH)

AF:

0.00427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00427

Hom.:

Bravo

AF:

0.00297

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.00436

EpiControl

AF:

0.00445

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

2.3

(source)

DANN

Benign

0.71

PhyloP100

-0.20

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

Computational scores

Splicing

Publications

Other links and lift over