chr1-11228701-G-A

Variant names:

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.2997C>T(p.Asn999Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.728 in 1,613,694 control chromosomes in the GnomAD database, including 433,703 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.65 ( 34109 hom., cov: 31)

Exomes 𝑓: 0.74 ( 399594 hom. )

Consequence

MTOR
NM_004958.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.749

Publications

67 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=-0.48).

BP6

Variant 1-11228701-G-A is Benign according to our data. Variant chr1-11228701-G-A is described in ClinVar as Benign. ClinVar VariationId is 1170840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.749 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.89 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTOR	NM_004958.4 link	c.2997C>T	p.Asn999Asn	synonymous_variant	Exon 19 of 58	ENST00000361445.9	NP_004949.1	P42345

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTOR	ENST00000361445.9 link	c.2997C>T	p.Asn999Asn	synonymous_variant	Exon 19 of 58	1	NM_004958.4	ENSP00000354558.4		P42345

Frequencies

GnomAD3 genomes

AF:

0.649

AC:

98586

AN:

151888

Hom.:

34091

Cov.:

show subpopulations

Gnomad AFR

AF:

0.386

Gnomad AMI

AF:

0.755

Gnomad AMR

AF:

0.780

Gnomad ASJ

AF:

0.655

Gnomad EAS

AF:

0.912

Gnomad SAS

AF:

0.831

Gnomad FIN

AF:

0.745

Gnomad MID

AF:

0.744

Gnomad NFE

AF:

0.728

Gnomad OTH

AF:

0.696

GnomAD2 exomes

AF:

0.751

AC:

188750

AN:

251254

AF XY:

0.755

show subpopulations

Gnomad AFR exome

AF:

0.373

Gnomad AMR exome

AF:

0.863

Gnomad ASJ exome

AF:

0.657

Gnomad EAS exome

AF:

0.919

Gnomad FIN exome

AF:

0.746

Gnomad NFE exome

AF:

0.733

Gnomad OTH exome

AF:

0.747

GnomAD4 exome

AF:

0.736

AC:

1075646

AN:

1461688

Hom.:

399594

Cov.:

AF XY:

0.738

AC XY:

536691

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.365

AC:

12222

AN:

33470

American (AMR)

AF:

0.852

AC:

38099

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.657

AC:

17170

AN:

26136

East Asian (EAS)

AF:

0.900

AC:

35712

AN:

39700

South Asian (SAS)

AF:

0.824

AC:

71040

AN:

86256

European-Finnish (FIN)

AF:

0.747

AC:

39914

AN:

53420

Middle Eastern (MID)

AF:

0.733

AC:

4214

AN:

5748

European-Non Finnish (NFE)

AF:

0.731

AC:

813223

AN:

1111850

Other (OTH)

AF:

0.729

AC:

44052

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

15610

31220

46829

62439

78049

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20064

40128

60192

80256

100320

<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:

0.649

AC:

98648

AN:

152006

Hom.:

34109

Cov.:

AF XY:

0.656

AC XY:

48775

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.386

AC:

16000

AN:

41422

American (AMR)

AF:

0.781

AC:

11928

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.655

AC:

2273

AN:

3468

East Asian (EAS)

AF:

0.912

AC:

4709

AN:

5166

South Asian (SAS)

AF:

0.831

AC:

4006

AN:

4820

European-Finnish (FIN)

AF:

0.745

AC:

7870

AN:

10564

Middle Eastern (MID)

AF:

0.752

AC:

221

AN:

294

European-Non Finnish (NFE)

AF:

0.728

AC:

49478

AN:

67976

Other (OTH)

AF:

0.700

AC:

1479

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1521

3043

4564

6086

7607

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

790

1580

2370

3160

3950

<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:

0.682

Hom.:

21011

Bravo

AF:

0.639

Asia WGS

AF:

0.854

AC:

2970

AN:

3478

EpiCase

AF:

0.726

EpiControl

AF:

0.731

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 06, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

2.8

(source)

DANN

Benign

0.80

PhyloP100

-0.75

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over