chr1-11130673-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004958.4(MTOR):c.5469C>T(p.Ala1823Ala) variant causes a synonymous change. The variant allele was found at a frequency of 0.0107 in 1,611,908 control chromosomes in the GnomAD database, including 596 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 165 hom., cov: 32)

Exomes 𝑓: 0.0088 ( 431 hom. )

Consequence

MTOR
NM_004958.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.63

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: 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 1-11130673-G-A is Benign according to our data. Variant chr1-11130673-G-A is described in ClinVar as Benign. ClinVar VariationId is 414896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0673 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.5469C>T	p.Ala1823Ala	synonymous	Exon 39 of 58	NP_004949.1
MTOR	NM_001386500.1		c.5469C>T	p.Ala1823Ala	synonymous	Exon 39 of 58	NP_001373429.1
MTOR	NM_001386501.1		c.4221C>T	p.Ala1407Ala	synonymous	Exon 38 of 57	NP_001373430.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MTOR	ENST00000361445.9	TSL:1 MANE Select	c.5469C>T	p.Ala1823Ala	synonymous	Exon 39 of 58	ENSP00000354558.4
MTOR	ENST00000934315.1		c.5523C>T	p.Ala1841Ala	synonymous	Exon 39 of 58	ENSP00000604374.1
MTOR	ENST00000934312.1		c.5490C>T	p.Ala1830Ala	synonymous	Exon 39 of 58	ENSP00000604371.1

Frequencies

GnomAD3 genomes

AF:

0.0288

AC:

4380

AN:

152050

Hom.:

162

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0645

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0708

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0446

Gnomad SAS

AF:

0.0666

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.0225

GnomAD2 exomes

AF:

0.0249

AC:

6041

AN:

242338

AF XY:

0.0236

show subpopulations

Gnomad AFR exome

AF:

0.0668

Gnomad AMR exome

AF:

0.0674

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0413

Gnomad FIN exome

AF:

0.0000476

Gnomad NFE exome

AF:

0.000398

Gnomad OTH exome

AF:

0.0180

GnomAD4 exome

AF:

0.00882

AC:

12870

AN:

1459740

Hom.:

431

Cov.:

AF XY:

0.00990

AC XY:

7189

AN XY:

725976

show subpopulations

African (AFR)

AF:

0.0667

AC:

2233

AN:

33458

American (AMR)

AF:

0.0660

AC:

2917

AN:

44180

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26008

East Asian (EAS)

AF:

0.0375

AC:

1487

AN:

39676

South Asian (SAS)

AF:

0.0585

AC:

5011

AN:

85710

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53326

Middle Eastern (MID)

AF:

0.00555

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000274

AC:

305

AN:

1111282

Other (OTH)

AF:

0.0147

AC:

884

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

875

1749

2624

3498

4373

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

200

400

600

800

1000

<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:

0.0289

AC:

4404

AN:

152168

Hom.:

165

Cov.:

AF XY:

0.0305

AC XY:

2268

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.0649

AC:

2694

AN:

41482

American (AMR)

AF:

0.0708

AC:

1082

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0447

AC:

231

AN:

5170

South Asian (SAS)

AF:

0.0660

AC:

318

AN:

4816

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000397

AC:

AN:

68024

Other (OTH)

AF:

0.0222

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

201

402

604

805

1006

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0104

Hom.:

Bravo

AF:

0.0336

Asia WGS

AF:

0.0620

AC:

218

AN:

3478

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

-0.50

CADD

Benign

6.2

(source)

DANN

Benign

0.53

PhyloP100

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over