NM_004958.4:c.5930C>T

Variant names:

• chr1-11128107-G-A
• rs587777893
• NM_004958.4:c.5930C>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_004958.4(MTOR):​c.5930C>T​(p.Thr1977Ile) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005902176: "In support of this prediction, in vitro functional studies showed that the p.Thr1977Ile variant activates mTOR complex 1 (mTORC1) signaling (Mirzaa GM et al., PMID:27159400)."; SCV001584148: Experimental studies have shown that this missense change affects MTOR function (PMID:27159400).; SCV002546733: Published functional studies demonstrate constitutive activation of mTOR complex 1 and enlarged neuronal size (Mirzaa et al., 2016); SCV006303685: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1977R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MTOR NM_004958.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.32
• Publications: 50 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Illumina
• overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005902176: "In support of this prediction, in vitro functional studies showed that the p.Thr1977Ile variant activates mTOR complex 1 (mTORC1) signaling (Mirzaa GM et al., PMID: 27159400)."; SCV001584148: Experimental studies have shown that this missense change affects MTOR function (PMID: 27159400).; SCV002546733: Published functional studies demonstrate constitutive activation of mTOR complex 1 and enlarged neuronal size (Mirzaa et al., 2016); SCV006303685: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_004958.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-11128107-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1296989.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867
• PP5: Variant 1-11128107-G-A is Pathogenic according to our data. Variant chr1-11128107-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 584432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTOR	NM_004958.4	MANE Select	c.5930C>T	p.Thr1977Ile	missense	Exon 43 of 58	NP_004949.1	P42345
	MTOR	NM_001386500.1		c.5930C>T	p.Thr1977Ile	missense	Exon 43 of 58	NP_001373429.1	P42345
	MTOR	NM_001386501.1		c.4682C>T	p.Thr1561Ile	missense	Exon 42 of 57	NP_001373430.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTOR	ENST00000361445.9	TSL:1 MANE Select	c.5930C>T	p.Thr1977Ile	missense	Exon 43 of 58	ENSP00000354558.4	P42345
	MTOR	ENST00000934315.1		c.5984C>T	p.Thr1995Ile	missense	Exon 43 of 58	ENSP00000604374.1
	MTOR	ENST00000934312.1		c.5951C>T	p.Thr1984Ile	missense	Exon 43 of 58	ENSP00000604371.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Isolated focal cortical dysplasia type II (2)
2	-	-	not provided (2)
1	-	-	CEBALID syndrome (1)
1	-	-	Isolated focal cortical dysplasia type II;C4225259:Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome (1)
1	-	-	MTOR-related disorder (1)
1	-	-	MTOR-related megalencephaly and pigmentary mosaicism in skin (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.085	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.45		Loss of ubiquitination at K1981 (P = 0.0481)
MVP		0.96
MPC		1.9
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.83
Mutation Taster		=4/96	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: rs587777893; hg19: chr1-11188164; COSMIC: COSV63868784; COSMIC: COSV63868784;