rs1057519917

Positions:

• chr1-11124517-A-G
• chr1-11124517-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Moderate

The NM_004958.4(MTOR):​c.6643T>C​(p.Ser2215Pro) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2215F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTOR NM_004958.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.84

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 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 chr1-11124516-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 156703.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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, 0.826
• PP5: Variant 1-11124517-A-G is Pathogenic according to our data. Variant chr1-11124517-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 451914.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTOR	NM_004958.4	c.6643T>C	p.Ser2215Pro	missense_variant	47/58	ENST00000361445.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTOR	ENST00000361445.9	c.6643T>C	p.Ser2215Pro	missense_variant	47/58	1	NM_004958.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 18, 2017

The S2215P variant in the MTOR gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The S2215P variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S2215P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret S2215P as a likely pathogenic variant -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Uncertain	2.6	.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.5	D;N
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		0.85	.;P
Vest4		0.84
MutPred		0.58		.;Gain of methylation at K2218 (P = 0.0619);
MVP		0.95
MPC		2.2
ClinPred		0.92	D
GERP RS		5.8
Varity_R		0.87
gMVP		0.97

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: rs1057519917; hg19: chr1-11184574; COSMIC: COSV63871622;