NM_004958.4:c.7255G>A

Variant names:

• chr1-11114363-C-T
• rs587777900
• NM_004958.4:c.7255G>A

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_004958.4(MTOR):​c.7255G>A​(p.Glu2419Lys) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005450383: Functional studies suggest a gain of function effect" and additional evidence is available in ClinVar. The gene MTOR is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTOR NM_004958.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 7.54
• Publications: 52 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

Specifications for MTOR are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005450383: Functional studies suggest a gain of function effect; however, additional evidence is needed to confirm this finding (Urano, 2007; Wagle, 2014).; SCV005902185: "In support of this prediction, in vitro functional studies showed that the p.Glu2419Lys variant increased kinase activity, leading to elevated levels of phosphorylated AKT and p70S6K, indicating that this variant impacts protein function (Carmignac V et al., PMID: 33833411; Mroske C et al., PMID: 26542245; Yang H et al., PMID: 23636326)."
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_004958.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant 1-11114363-C-T is Pathogenic according to our data. Variant chr1-11114363-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 156709.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.7255G>A	p.Glu2419Lys	missense	Exon 53 of 58	NP_004949.1	P42345
	MTOR	NM_001386500.1		c.7255G>A	p.Glu2419Lys	missense	Exon 53 of 58	NP_001373429.1	P42345
	MTOR	NM_001386501.1		c.6007G>A	p.Glu2003Lys	missense	Exon 52 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.7255G>A	p.Glu2419Lys	missense	Exon 53 of 58	ENSP00000354558.4	P42345
	MTOR	ENST00000934315.1		c.7309G>A	p.Glu2437Lys	missense	Exon 53 of 58	ENSP00000604374.1
	MTOR	ENST00000934312.1		c.7276G>A	p.Glu2426Lys	missense	Exon 53 of 58	ENSP00000604371.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	CEBALID syndrome (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome (1)
1	-	-	not provided (2)
1	-	-	Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.033	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.80		Gain of ubiquitination at E2419 (P = 0.0276)
MVP		0.96
MPC		2.6
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.93
gMVP		0.98
Mutation Taster		=9/91	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: rs587777900; hg19: chr1-11174420; COSMIC: COSV63869451;