NM_004958.4:c.5395G>A

Variant names:

• chr1-11130747-C-T
• rs863225264
• NM_004958.4:c.5395G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_004958.4(MTOR):​c.5395G>A​(p.Glu1799Lys) 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: "SCV001786563: "experiments in patient cells, human cell lines, and cultured rodent neurons have confirmed a gain-of-function effect of the p.Glu1799Lys variant (Grabiner et al. 2014" and additional evidence is available in ClinVar. The gene MTOR is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MTOR NM_004958.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:21 O:1
• Conservation: PhyloP100: 7.53
• Publications: 67 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 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001786563: "experiments in patient cells, human cell lines, and cultured rodent neurons have confirmed a gain-of-function effect of the p.Glu1799Lys variant (Grabiner et al. 2014; Baynam et al. 2015; Mirzaa et al. 2016)."; SCV006101424: This variant results in constitutive activation of MTOR protein (Mirzaa_2016). PMID: 27159400; SCV000321909: Functional studies indicate that E1799K results in an increase in mTOR pathway activity, suggesting a gain-of-function mechanism of disease (Baynam, et al., 2015); SCV000965481: Experimental studies have shown that this missense change affects MTOR function (PMID: 24631838, 25851998).; SCV000741517: Functional analysis demonstrated that the p.E1799K alteration, which was originally identified in somatic tumor samples, results in activation of MTOR. Expression of MTOR with the p.E1799K alteration in HEK293 cells results in increased MTOR kinase activity towards AKT and 4E-Binding Protein 1, suggesting a gain-of-function effect (Grabiner, 2014).
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_004958.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854
• PP5: Variant 1-11130747-C-T is Pathogenic according to our data. Variant chr1-11130747-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 217823.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.5395G>A	p.Glu1799Lys	missense	Exon 39 of 58	NP_004949.1	P42345
	MTOR	NM_001386500.1		c.5395G>A	p.Glu1799Lys	missense	Exon 39 of 58	NP_001373429.1	P42345
	MTOR	NM_001386501.1		c.4147G>A	p.Glu1383Lys	missense	Exon 38 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.5395G>A	p.Glu1799Lys	missense	Exon 39 of 58	ENSP00000354558.4	P42345
	MTOR	ENST00000934315.1		c.5449G>A	p.Glu1817Lys	missense	Exon 39 of 58	ENSP00000604374.1
	MTOR	ENST00000934312.1		c.5416G>A	p.Glu1806Lys	missense	Exon 39 of 58	ENSP00000604371.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 191474 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1428360 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 707194

African (AFR) AF: 0.00 AC: 0 AN: 33052

American (AMR) AF: 0.00 AC: 0 AN: 38650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25450

East Asian (EAS) AF: 0.00 AC: 0 AN: 38618

South Asian (SAS) AF: 0.00 AC: 0 AN: 81934

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51204

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094538

Other (OTH) AF: 0.00 AC: 0 AN: 59192

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome (10)
4	-	-	not provided (4)
2	-	-	Intellectual disability (2)
1	-	-	CEBALID syndrome (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Isolated focal cortical dysplasia type II (1)
1	-	-	Isolated focal cortical dysplasia type II;C4225259:Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome (1)
1	-	-	Rare genetic intellectual disability (1)
1	-	-	Severe intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	2.0	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.88	P
Vest4		0.78
MutPred		0.77		Gain of MoRF binding (P = 0.0028)
MVP		0.91
MPC		2.0
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.61
gMVP		0.67
Mutation Taster		=17/83	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: rs863225264; hg19: chr1-11190804; COSMIC: COSV63869964; COSMIC: COSV63869964;