1-11130640-CGTGGTGGCGGCA-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4BP6_Very_StrongBS1BS2

The NM_004958.4(MTOR):​c.5490_5501delTGCCGCCACCAC​(p.Ala1831_Thr1834del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000646 in 1,613,568 control chromosomes in the GnomAD database, including 5 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1830T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00059 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00065 ( 4 hom. )

Consequence

MTOR
NM_004958.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 3.78

Publications

2 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

PM4
Nonframeshift variant in NON repetitive region in NM_004958.4.
BP6
Variant 1-11130640-CGTGGTGGCGGCA-C is Benign according to our data. Variant chr1-11130640-CGTGGTGGCGGCA-C is described in ClinVar as [Benign]. Clinvar id is 414898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000585 (89/152044) while in subpopulation EAS AF = 0.00775 (40/5160). AF 95% confidence interval is 0.00585. There are 1 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High AC in GnomAd4 at 89 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MTORNM_004958.4 linkc.5490_5501delTGCCGCCACCAC p.Ala1831_Thr1834del disruptive_inframe_deletion Exon 39 of 58 ENST00000361445.9 NP_004949.1 P42345

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MTORENST00000361445.9 linkc.5490_5501delTGCCGCCACCAC p.Ala1831_Thr1834del disruptive_inframe_deletion Exon 39 of 58 1 NM_004958.4 ENSP00000354558.4 P42345

Frequencies

GnomAD3 genomes
AF:
0.000586
AC:
89
AN:
151926
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000725
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00773
Gnomad SAS
AF:
0.000208
Gnomad FIN
AF:
0.0000943
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000589
Gnomad OTH
AF:
0.000959
GnomAD2 exomes
AF:
0.00111
AC:
275
AN:
247814
AF XY:
0.00110
show subpopulations
Gnomad AFR exome
AF:
0.000186
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0107
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000506
Gnomad OTH exome
AF:
0.000657
GnomAD4 exome
AF:
0.000652
AC:
953
AN:
1461524
Hom.:
4
AF XY:
0.000686
AC XY:
499
AN XY:
727062
show subpopulations
African (AFR)
AF:
0.000209
AC:
7
AN:
33468
American (AMR)
AF:
0.0000895
AC:
4
AN:
44684
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26104
East Asian (EAS)
AF:
0.00504
AC:
200
AN:
39700
South Asian (SAS)
AF:
0.000406
AC:
35
AN:
86176
European-Finnish (FIN)
AF:
0.0000562
AC:
3
AN:
53376
Middle Eastern (MID)
AF:
0.000173
AC:
1
AN:
5766
European-Non Finnish (NFE)
AF:
0.000592
AC:
658
AN:
1111874
Other (OTH)
AF:
0.000745
AC:
45
AN:
60376
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.447
Heterozygous variant carriers
0
64
128
191
255
319
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
32
64
96
128
160
<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:
0.000585
AC:
89
AN:
152044
Hom.:
1
Cov.:
32
AF XY:
0.000552
AC XY:
41
AN XY:
74334
show subpopulations
African (AFR)
AF:
0.0000723
AC:
3
AN:
41492
American (AMR)
AF:
0.000131
AC:
2
AN:
15262
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3464
East Asian (EAS)
AF:
0.00775
AC:
40
AN:
5160
South Asian (SAS)
AF:
0.000208
AC:
1
AN:
4798
European-Finnish (FIN)
AF:
0.0000943
AC:
1
AN:
10606
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.000589
AC:
40
AN:
67948
Other (OTH)
AF:
0.000949
AC:
2
AN:
2108
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.482
Heterozygous variant carriers
0
5
11
16
22
27
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.000400
Hom.:
0
Bravo
AF:
0.000778
EpiCase
AF:
0.000600
EpiControl
AF:
0.000653

ClinVar

Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Oct 28, 2020
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jun 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

MTOR: BS1, BS2 -

Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
3.8
Mutation Taster
=176/24
polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs571156267; hg19: chr1-11190697; COSMIC: COSV63868577; COSMIC: COSV63868577; API