rs2536

Variant names:

• chr1-11106656-T-C
• rs2536
• NM_004958.4:c.*829A>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.*829A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0321 in 1,105,044 control chromosomes in the GnomAD database, including 991 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (374 hom., cov: 32)
  • Exomes 𝑓: 0.028 (617 hom.)
• Consequence: MTOR NM_004958.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.593
• Publications: 66 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=-0.86).
• BP6: Variant 1-11106656-T-C is Benign according to our data. Variant chr1-11106656-T-C is described in ClinVar as Benign. ClinVar VariationId is 1237596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTOR	NM_004958.4	c.*829A>G		3_prime_UTR_variant	Exon 58 of 58	ENST00000361445.9	NP_004949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTOR	ENST00000361445.9	c.*829A>G		3_prime_UTR_variant	Exon 58 of 58	1	NM_004958.4	ENSP00000354558.4

Frequencies

GnomAD3 genomes AF: 0.0590 AC: 8974 AN: 152168 Hom.: 369 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.0614

Gnomad ASJ AF: 0.0691

Gnomad EAS AF: 0.0854

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.0530

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0233

Gnomad OTH AF: 0.0664

GnomAD4 exome AF: 0.0278 AC: 26517 AN: 952758 Hom.: 617 Cov.: 30 AF XY: 0.0280 AC XY: 12395 AN XY: 442320

African (AFR) AF: 0.115 AC: 2409 AN: 20924

American (AMR) AF: 0.0680 AC: 458 AN: 6740

Ashkenazi Jewish (ASJ) AF: 0.0809 AC: 892 AN: 11026

East Asian (EAS) AF: 0.0628 AC: 1090 AN: 17344

South Asian (SAS) AF: 0.110 AC: 2419 AN: 22048

European-Finnish (FIN) AF: 0.0486 AC: 102 AN: 2100

Middle Eastern (MID) AF: 0.0570 AC: 127 AN: 2230

European-Non Finnish (NFE) AF: 0.0207 AC: 17276 AN: 834204

Other (OTH) AF: 0.0483 AC: 1744 AN: 36142

GnomAD4 genome AF: 0.0591 AC: 8994 AN: 152286 Hom.: 374 Cov.: 32 AF XY: 0.0615 AC XY: 4578 AN XY: 74464

African (AFR) AF: 0.107 AC: 4438 AN: 41542

American (AMR) AF: 0.0618 AC: 944 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0691 AC: 240 AN: 3472

East Asian (EAS) AF: 0.0854 AC: 443 AN: 5186

South Asian (SAS) AF: 0.124 AC: 598 AN: 4824

European-Finnish (FIN) AF: 0.0530 AC: 563 AN: 10614

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0233 AC: 1588 AN: 68044

Other (OTH) AF: 0.0672 AC: 142 AN: 2114

Alfa AF: 0.0346 Hom.: 218

Bravo AF: 0.0610

Asia WGS AF: 0.111 AC: 386 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 23, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29978580) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	8.5
DANN	Benign	0.80
PhyloP100		0.59
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: rs2536; hg19: chr1-11166713; COSMIC: COSV63868658;