1-11111169-C-T

Variant names:

• chr1-11111169-C-T
• rs17036350
• NM_004958.4:c.7367-1440G>A

Variant summary

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

The NM_004958.4(MTOR):​c.7367-1440G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0827 in 455,678 control chromosomes in the GnomAD database, including 2,895 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 0.097 (1205 hom., cov: 31)
  • Exomes 𝑓: 0.076 (1690 hom.)
• Consequence: MTOR NM_004958.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.745
• Publications: 17 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004958.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTOR	NM_004958.4	MANE Select	c.7367-1440G>A		intron	N/A	NP_004949.1
	MTOR	NM_001386500.1		c.7367-1440G>A		intron	N/A	NP_001373429.1
	MTOR	NM_001386501.1		c.6119-1440G>A		intron	N/A	NP_001373430.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTOR	ENST00000361445.9	TSL:1 MANE Select	c.7367-1440G>A		intron	N/A	ENSP00000354558.4
	MTOR	ENST00000703143.2		c.7367-1440G>A		intron	N/A	ENSP00000515200.2
	MTOR	ENST00000703140.1		c.7154-1440G>A		intron	N/A	ENSP00000515197.1

Frequencies

GnomAD3 genomes AF: 0.0967 AC: 14692 AN: 151990 Hom.: 1194 Cov.: 31

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.0692

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.0535

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0238

Gnomad OTH AF: 0.0985

GnomAD2 exomes AF: 0.0951 AC: 12157 AN: 127806 AF XY: 0.0948

Gnomad AFR exome AF: 0.199

Gnomad AMR exome AF: 0.141

Gnomad ASJ exome AF: 0.0819

Gnomad EAS exome AF: 0.127

Gnomad FIN exome AF: 0.0533

Gnomad NFE exome AF: 0.0226

Gnomad OTH exome AF: 0.0760

GnomAD4 exome AF: 0.0756 AC: 22949 AN: 303570 Hom.: 1690 Cov.: 0 AF XY: 0.0824 AC XY: 14239 AN XY: 172882

African (AFR) AF: 0.194 AC: 1670 AN: 8588

American (AMR) AF: 0.140 AC: 3822 AN: 27242

Ashkenazi Jewish (ASJ) AF: 0.0798 AC: 861 AN: 10784

East Asian (EAS) AF: 0.124 AC: 1139 AN: 9194

South Asian (SAS) AF: 0.172 AC: 10247 AN: 59706

European-Finnish (FIN) AF: 0.0532 AC: 658 AN: 12364

Middle Eastern (MID) AF: 0.0526 AC: 146 AN: 2776

European-Non Finnish (NFE) AF: 0.0212 AC: 3371 AN: 158706

Other (OTH) AF: 0.0728 AC: 1035 AN: 14210

GnomAD4 genome AF: 0.0969 AC: 14742 AN: 152108 Hom.: 1205 Cov.: 31 AF XY: 0.102 AC XY: 7556 AN XY: 74370

African (AFR) AF: 0.202 AC: 8368 AN: 41472

American (AMR) AF: 0.135 AC: 2067 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0692 AC: 240 AN: 3470

East Asian (EAS) AF: 0.131 AC: 676 AN: 5172

South Asian (SAS) AF: 0.198 AC: 955 AN: 4826

European-Finnish (FIN) AF: 0.0535 AC: 567 AN: 10594

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0238 AC: 1620 AN: 67998

Other (OTH) AF: 0.0989 AC: 208 AN: 2104

Alfa AF: 0.0495 Hom.: 904

Bravo AF: 0.104

Asia WGS AF: 0.181 AC: 631 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.37
DANN	Benign	0.26
PhyloP100		-0.74
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: rs17036350; hg19: chr1-11171226; COSMIC: COSV63868668;