1-11124517-A-T

Variant names:

• chr1-11124517-A-T
• rs1057519917
• NM_004958.4:c.6643T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_004958.4(MTOR):​c.6643T>A​(p.Ser2215Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2215Y) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTOR NM_004958.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:7
• Conservation: PhyloP100: 8.84
• Publications: 6 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-11124516-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 376129.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3716551).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTOR	NM_004958.4	c.6643T>A	p.Ser2215Thr	missense_variant	Exon 47 of 58	ENST00000361445.9	NP_004949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTOR	ENST00000361445.9	c.6643T>A	p.Ser2215Thr	missense_variant	Exon 47 of 58	1	NM_004958.4	ENSP00000354558.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: no assertion criteria provided

Submissions by phenotype

Glioblastoma Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Papillary renal cell carcinoma, sporadic Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Malignant neoplasm of body of uterus Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Papillary renal cell carcinoma type 1 Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Neoplasm of uterine cervix Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Malignant melanoma of skin Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Neoplasm of the large intestine Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Benign	0.45
DEOGEN2	Benign	0.23	T;T
Eigen	Benign	-0.31
Eigen_PC	Benign	0.013
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.37	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.78	.;N
PhyloP100		8.8
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	2.8	N;N
REVEL	Benign	0.28
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0050	.;B
Vest4		0.66
MutPred		0.43		.;Loss of disorder (P = 0.0773);
MVP		0.80
MPC		1.2
ClinPred		0.75	D
GERP RS		5.8
Varity_R		0.42
gMVP		0.80
Mutation Taster		=58/42	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057519917; hg19: chr1-11184574; COSMIC: COSV100815980;