chr1-11117039-C-T

Position:

• chr1-11117039-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_004958.4(MTOR):​c.6981G>A​(p.Met2327Ile) 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTOR NM_004958.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.35

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MTOR. . Gene score misZ 7.0206 (greater than the threshold 3.09). Trascript score misZ 9.4864 (greater than threshold 3.09). GenCC has associacion of gene with macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923
• PP5: Variant 1-11117039-C-T is Pathogenic according to our data. Variant chr1-11117039-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 242349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTOR	NM_004958.4	c.6981G>A	p.Met2327Ile	missense_variant	50/58	ENST00000361445.9	NP_004949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTOR	ENST00000361445.9	c.6981G>A	p.Met2327Ile	missense_variant	50/58	1	NM_004958.4	ENSP00000354558	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2023	Published functional studies demonstrate that M2371I leads to a significant increase in kinase activity (Rodrik-Outmezguine et al., 2016); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26956871, 27635236, 28699534, 28892148, 27920721, 26504747, 27482884, 25576899, 27830187, 33935721, 27279227, 28554332) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 04, 2021	For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect MTOR protein function (PMID: 27279227). This variant has been observed in individual(s) with clinical features of Smith-Kingsmore syndrome (PMID: 28554332, 27830187, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 242349). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with isoleucine at codon 2327 of the MTOR protein (p.Met2327Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. -

Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jun 09, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 16, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.9	.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	.;D
Vest4		0.94
MutPred		0.77		.;Loss of phosphorylation at Y2332 (P = 0.1632);
MVP		0.96
MPC		2.6
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.93
gMVP		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs878855328; hg19: chr1-11177096; COSMIC: COSV63868602; COSMIC: COSV63868602;