Genetic Variant MTOR:p.Asn2043Asn (chr1-11127711-G-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_004958.4(MTOR):c.6129C>T(p.Asn2043Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000615 in 1,614,008 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0035 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 2 hom. )

Consequence

MTOR
NM_004958.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.453

Publications

0 publications found

Variant links:

COSMIC-nc: COSV104671802

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 1-11127711-G-A is Benign according to our data. Variant chr1-11127711-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 414905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.453 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00349 (531/152160) while in subpopulation AFR AF = 0.0121 (502/41492). AF 95% confidence interval is 0.0112. There are 5 homozygotes in GnomAd4. There are 278 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 531 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
MTOR	NM_004958.4	MANE Select	c.6129C>T	p.Asn2043Asn	synonymous	Exon 44 of 58	NP_004949.1
MTOR	NM_001386500.1		c.6129C>T	p.Asn2043Asn	synonymous	Exon 44 of 58	NP_001373429.1
MTOR	NM_001386501.1		c.4881C>T	p.Asn1627Asn	synonymous	Exon 43 of 57	NP_001373430.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MTOR	ENST00000361445.9	TSL:1 MANE Select	c.6129C>T	p.Asn2043Asn	synonymous	Exon 44 of 58	ENSP00000354558.4
MTOR	ENST00000703143.2		c.6129C>T	p.Asn2043Asn	synonymous	Exon 44 of 58	ENSP00000515200.2
MTOR	ENST00000703140.1		c.5916C>T	p.Asn1972Asn	synonymous	Exon 42 of 56	ENSP00000515197.1

Frequencies

GnomAD3 genomes

AF:

0.00347

AC:

527

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0120

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.000879

AC:

221

AN:

251428

AF XY:

0.000633

show subpopulations

Gnomad AFR exome

AF:

0.0112

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000316

AC:

462

AN:

1461848

Hom.:

Cov.:

AF XY:

0.000275

AC XY:

200

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.0106

AC:

356

AN:

33480

American (AMR)

AF:

0.000738

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1112008

Other (OTH)

AF:

0.000878

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

119

149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00349

AC:

531

AN:

152160

Hom.:

Cov.:

AF XY:

0.00374

AC XY:

278

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.0121

AC:

502

AN:

41492

American (AMR)

AF:

0.00118

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68010

Other (OTH)

AF:

0.00427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

110

138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00190

Hom.:

Bravo

AF:

0.00394

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Sep 09, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MTOR: BP4, BP7, BS1, BS2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

7.4

(source)

DANN

Benign

0.72

PhyloP100

0.45

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=94/6

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over