1-11205660-A-G

Variant names:

• chr1-11205660-A-G
• rs2300095
• NM_004958.4:c.3802-957T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004958.4(MTOR):​c.3802-957T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.63 in 152,138 control chromosomes in the GnomAD database, including 32,243 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.63 (32243 hom., cov: 33)
• Consequence: MTOR NM_004958.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0210
• Publications: 16 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.89 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTOR	NM_004958.4	c.3802-957T>C		intron_variant	Intron 25 of 57	ENST00000361445.9	NP_004949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTOR	ENST00000361445.9	c.3802-957T>C		intron_variant	Intron 25 of 57	1	NM_004958.4	ENSP00000354558.4

Frequencies

GnomAD3 genomes AF: 0.630 AC: 95778 AN: 152020 Hom.: 32225 Cov.: 33

Gnomad AFR AF: 0.371

Gnomad AMI AF: 0.752

Gnomad AMR AF: 0.759

Gnomad ASJ AF: 0.644

Gnomad EAS AF: 0.912

Gnomad SAS AF: 0.826

Gnomad FIN AF: 0.709

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.706

Gnomad OTH AF: 0.680

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.630 AC: 95836 AN: 152138 Hom.: 32243 Cov.: 33 AF XY: 0.637 AC XY: 47355 AN XY: 74356

African (AFR) AF: 0.371 AC: 15390 AN: 41478

American (AMR) AF: 0.760 AC: 11618 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.644 AC: 2235 AN: 3470

East Asian (EAS) AF: 0.911 AC: 4730 AN: 5190

South Asian (SAS) AF: 0.826 AC: 3974 AN: 4810

European-Finnish (FIN) AF: 0.709 AC: 7491 AN: 10568

Middle Eastern (MID) AF: 0.759 AC: 223 AN: 294

European-Non Finnish (NFE) AF: 0.706 AC: 48043 AN: 68008

Other (OTH) AF: 0.683 AC: 1446 AN: 2116

Alfa AF: 0.654 Hom.: 4210

Bravo AF: 0.622

Asia WGS AF: 0.850 AC: 2957 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.0
DANN	Benign	0.57
PhyloP100		0.021
Mutation Taster		=100/0	polymorphism (auto)

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: rs2300095; hg19: chr1-11265717;