NM_004958.4:c.2209-152A>T

Variant names:

• chr1-11234417-T-A
• rs718206
• NM_004958.4:c.2209-152A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004958.4(MTOR):​c.2209-152A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.718 in 843,986 control chromosomes in the GnomAD database, including 224,584 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (33811 hom., cov: 32)
  • Exomes 𝑓: 0.74 (190773 hom.)
• Consequence: MTOR NM_004958.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.184
• Publications: 21 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-11234417-T-A is Benign according to our data. Variant chr1-11234417-T-A is described in ClinVar as Benign. ClinVar VariationId is 1239514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.2209-152A>T		intron_variant	Intron 13 of 57	ENST00000361445.9	NP_004949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTOR	ENST00000361445.9	c.2209-152A>T		intron_variant	Intron 13 of 57	1	NM_004958.4	ENSP00000354558.4

Frequencies

GnomAD3 genomes AF: 0.643 AC: 97793 AN: 152040 Hom.: 33796 Cov.: 32

Gnomad AFR AF: 0.366

Gnomad AMI AF: 0.752

Gnomad AMR AF: 0.779

Gnomad ASJ AF: 0.656

Gnomad EAS AF: 0.912

Gnomad SAS AF: 0.834

Gnomad FIN AF: 0.745

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.728

Gnomad OTH AF: 0.690

GnomAD4 exome AF: 0.735 AC: 508512 AN: 691830 Hom.: 190773 AF XY: 0.739 AC XY: 264365 AN XY: 357846

African (AFR) AF: 0.340 AC: 6056 AN: 17834

American (AMR) AF: 0.841 AC: 21888 AN: 26026

Ashkenazi Jewish (ASJ) AF: 0.657 AC: 10169 AN: 15472

East Asian (EAS) AF: 0.898 AC: 31604 AN: 35190

South Asian (SAS) AF: 0.827 AC: 44876 AN: 54288

European-Finnish (FIN) AF: 0.745 AC: 25667 AN: 34450

Middle Eastern (MID) AF: 0.718 AC: 2638 AN: 3674

European-Non Finnish (NFE) AF: 0.724 AC: 340754 AN: 470614

Other (OTH) AF: 0.725 AC: 24860 AN: 34282

GnomAD4 genome AF: 0.643 AC: 97845 AN: 152156 Hom.: 33811 Cov.: 32 AF XY: 0.650 AC XY: 48371 AN XY: 74404

African (AFR) AF: 0.366 AC: 15164 AN: 41484

American (AMR) AF: 0.779 AC: 11911 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.656 AC: 2276 AN: 3470

East Asian (EAS) AF: 0.912 AC: 4728 AN: 5186

South Asian (SAS) AF: 0.834 AC: 4023 AN: 4826

European-Finnish (FIN) AF: 0.745 AC: 7898 AN: 10600

Middle Eastern (MID) AF: 0.753 AC: 220 AN: 292

European-Non Finnish (NFE) AF: 0.728 AC: 49475 AN: 67990

Other (OTH) AF: 0.693 AC: 1464 AN: 2112

Alfa AF: 0.670 Hom.: 4439

Bravo AF: 0.633

Asia WGS AF: 0.852 AC: 2965 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.84
DANN	Benign	0.64
PhyloP100		0.18
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: rs718206; hg19: chr1-11294474;