rs1057519917

Variant names:

• chr1-11124517-A-G
• rs1057519917
• NM_004958.4:c.6643T>C

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 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. S2215Y) 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
• Publications: 6 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet, 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: Likely_pathogenic. The variant received 7 ACMG points.

• 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-T is described in ClinVar as Pathogenic. ClinVar VariationId is 376129.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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 VariationId is 451914.Status of the report is criteria_provided_single_submitter, 1 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.6643T>C	p.Ser2215Pro	missense	Exon 47 of 58	NP_004949.1	P42345
	MTOR	NM_001386500.1		c.6643T>C	p.Ser2215Pro	missense	Exon 47 of 58	NP_001373429.1	P42345
	MTOR	NM_001386501.1		c.5395T>C	p.Ser1799Pro	missense	Exon 46 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.6643T>C	p.Ser2215Pro	missense	Exon 47 of 58	ENSP00000354558.4	P42345
	MTOR	ENST00000934315.1		c.6697T>C	p.Ser2233Pro	missense	Exon 47 of 58	ENSP00000604374.1
	MTOR	ENST00000934312.1		c.6664T>C	p.Ser2222Pro	missense	Exon 47 of 58	ENSP00000604371.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		8.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.014	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
Mutation Taster		=32/68	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: rs1057519917; hg19: chr1-11184574;