1-11228701-G-T

Variant names:

• chr1-11228701-G-T
• rs1064261
• NM_004958.4:c.2997C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004958.4(MTOR):​c.2997C>A​(p.Asn999Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. N999H) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MTOR NM_004958.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.749
• 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: 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTOR	NM_004958.4	c.2997C>A	p.Asn999Lys	missense_variant	Exon 19 of 58	ENST00000361445.9	NP_004949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTOR	ENST00000361445.9	c.2997C>A	p.Asn999Lys	missense_variant	Exon 19 of 58	1	NM_004958.4	ENSP00000354558.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 61

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 21011

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.28	N
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		-0.75
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.24
Sift	Benign	0.30	T
Sift4G	Benign	0.40	T
Polyphen		0.92	P
Vest4		0.64
MutPred		0.53		Gain of ubiquitination at N999 (P = 0.0276);
MVP		0.63
MPC		0.95
ClinPred		0.91	D
GERP RS		-2.4
Varity_R		0.58
gMVP		0.64
Mutation Taster		=59/41	polymorphism

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: rs1064261; hg19: chr1-11288758;