rs2024627

Variant names:

• chr1-11238733-T-C
• rs2024627
• NM_004958.4:c.1787-116A>G

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.1787-116A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.722 in 796,032 control chromosomes in the GnomAD database, including 213,069 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (33999 hom., cov: 30)
  • Exomes 𝑓: 0.74 (179070 hom.)
• Consequence: MTOR NM_004958.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.887
• Publications: 20 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=-0.88).
• BP6: Variant 1-11238733-T-C is Benign according to our data. Variant chr1-11238733-T-C is described in ClinVar as Benign. ClinVar VariationId is 1225397.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.1787-116A>G		intron_variant	Intron 11 of 57	ENST00000361445.9	NP_004949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTOR	ENST00000361445.9	c.1787-116A>G		intron_variant	Intron 11 of 57	1	NM_004958.4	ENSP00000354558.4

Frequencies

GnomAD3 genomes AF: 0.649 AC: 98256 AN: 151444 Hom.: 33982 Cov.: 30

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.752

Gnomad AMR AF: 0.780

Gnomad ASJ AF: 0.655

Gnomad EAS AF: 0.912

Gnomad SAS AF: 0.833

Gnomad FIN AF: 0.745

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.728

Gnomad OTH AF: 0.696

GnomAD4 exome AF: 0.740 AC: 476630 AN: 644474 Hom.: 179070 AF XY: 0.743 AC XY: 245382 AN XY: 330238

African (AFR) AF: 0.368 AC: 5957 AN: 16182

American (AMR) AF: 0.835 AC: 19075 AN: 22840

Ashkenazi Jewish (ASJ) AF: 0.657 AC: 10203 AN: 15522

East Asian (EAS) AF: 0.898 AC: 28545 AN: 31800

South Asian (SAS) AF: 0.826 AC: 42378 AN: 51278

European-Finnish (FIN) AF: 0.749 AC: 32780 AN: 43766

Middle Eastern (MID) AF: 0.734 AC: 2009 AN: 2736

European-Non Finnish (NFE) AF: 0.729 AC: 312183 AN: 428140

Other (OTH) AF: 0.730 AC: 23500 AN: 32210

GnomAD4 genome AF: 0.649 AC: 98317 AN: 151558 Hom.: 33999 Cov.: 30 AF XY: 0.656 AC XY: 48533 AN XY: 73994

African (AFR) AF: 0.386 AC: 15940 AN: 41336

American (AMR) AF: 0.781 AC: 11893 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.655 AC: 2274 AN: 3470

East Asian (EAS) AF: 0.912 AC: 4693 AN: 5148

South Asian (SAS) AF: 0.833 AC: 4019 AN: 4822

European-Finnish (FIN) AF: 0.745 AC: 7698 AN: 10338

Middle Eastern (MID) AF: 0.760 AC: 222 AN: 292

European-Non Finnish (NFE) AF: 0.728 AC: 49421 AN: 67900

Other (OTH) AF: 0.699 AC: 1473 AN: 2106

Alfa AF: 0.654 Hom.: 5167

Bravo AF: 0.639

Asia WGS AF: 0.853 AC: 2969 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	-0.88
CADD	Benign	0.33
DANN	Benign	0.53
PhyloP100		-0.89
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: rs2024627; hg19: chr1-11298790;