rs6701524

Variant names:

• chr1-11138445-A-G
• rs6701524
• NM_004958.4:c.5130+859T>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.5130+859T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 152,142 control chromosomes in the GnomAD database, including 8,279 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 0.30 (8279 hom., cov: 32)
• Consequence: MTOR NM_004958.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.526
• 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Illumina
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.506 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTOR	NM_004958.4	MANE Select	c.5130+859T>C		intron	N/A	NP_004949.1	P42345
	MTOR	NM_001386500.1		c.5130+859T>C		intron	N/A	NP_001373429.1	P42345
	MTOR	NM_001386501.1		c.3882+859T>C		intron	N/A	NP_001373430.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTOR	ENST00000361445.9	TSL:1 MANE Select	c.5130+859T>C		intron	N/A	ENSP00000354558.4	P42345
	MTOR	ENST00000934315.1		c.5184+859T>C		intron	N/A	ENSP00000604374.1
	MTOR	ENST00000934312.1		c.5151+859T>C		intron	N/A	ENSP00000604371.1

Frequencies

GnomAD3 genomes AF: 0.303 AC: 45992 AN: 152024 Hom.: 8270 Cov.: 32

Gnomad AFR AF: 0.512

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.0860

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.272

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

GnomAD4 genome AF: 0.303 AC: 46029 AN: 152142 Hom.: 8279 Cov.: 32 AF XY: 0.296 AC XY: 22022 AN XY: 74394

African (AFR) AF: 0.511 AC: 21199 AN: 41460

American (AMR) AF: 0.193 AC: 2951 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 1143 AN: 3472

East Asian (EAS) AF: 0.0862 AC: 447 AN: 5188

South Asian (SAS) AF: 0.161 AC: 775 AN: 4818

European-Finnish (FIN) AF: 0.228 AC: 2412 AN: 10598

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.240 AC: 16289 AN: 68004

Other (OTH) AF: 0.269 AC: 569 AN: 2114

Alfa AF: 0.258 Hom.: 7134

Bravo AF: 0.310

Asia WGS AF: 0.136 AC: 473 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.072
DANN	Benign	0.78
PhyloP100		-0.53
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: rs6701524; hg19: chr1-11198502;