1-11130747-C-G

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_004958.4(MTOR):​c.5395G>C​(p.Glu1799Gln) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1799K) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MTOR NM_004958.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.53
• Publications: 0 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: Illumina, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• 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 8 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, 3 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 chr1-11130747-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.857

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTOR	NM_004958.4	MANE Select	c.5395G>C	p.Glu1799Gln	missense	Exon 39 of 58	NP_004949.1
	MTOR	NM_001386500.1		c.5395G>C	p.Glu1799Gln	missense	Exon 39 of 58	NP_001373429.1
	MTOR	NM_001386501.1		c.4147G>C	p.Glu1383Gln	missense	Exon 38 of 57	NP_001373430.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTOR	ENST00000361445.9	TSL:1 MANE Select	c.5395G>C	p.Glu1799Gln	missense	Exon 39 of 58	ENSP00000354558.4
	MTOR	ENST00000934315.1		c.5449G>C	p.Glu1817Gln	missense	Exon 39 of 58	ENSP00000604374.1
	MTOR	ENST00000934312.1		c.5416G>C	p.Glu1806Gln	missense	Exon 39 of 58	ENSP00000604371.1

Frequencies

GnomAD3 genomes Cov.: 32

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.74		Gain of MoRF binding (P = 0.0217)
MVP		0.81
MPC		1.9
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.59
gMVP		0.45
Mutation Taster		=37/63	disease causing

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;