rs10492975

Variant names:

• chr1-11175419-A-G
• rs10492975
• NM_004958.4:c.4254-7902T>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.4254-7902T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0572 in 152,298 control chromosomes in the GnomAD database, including 349 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 0.057 (349 hom., cov: 32)
• Consequence: MTOR NM_004958.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.347
• Publications: 3 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=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.111 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.4254-7902T>C		intron	N/A	NP_004949.1
	MTOR	NM_001386500.1		c.4254-7902T>C		intron	N/A	NP_001373429.1
	MTOR	NM_001386501.1		c.3006-7902T>C		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.4254-7902T>C		intron	N/A	ENSP00000354558.4
	MTOR	ENST00000703143.2		c.4254-7902T>C		intron	N/A	ENSP00000515200.2
	MTOR	ENST00000703140.1		c.4041-7902T>C		intron	N/A	ENSP00000515197.1

Frequencies

GnomAD3 genomes AF: 0.0571 AC: 8694 AN: 152180 Hom.: 345 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0607

Gnomad ASJ AF: 0.0542

Gnomad EAS AF: 0.0855

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.0525

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0224

Gnomad OTH AF: 0.0636

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

GnomAD4 genome AF: 0.0572 AC: 8707 AN: 152298 Hom.: 349 Cov.: 32 AF XY: 0.0595 AC XY: 4433 AN XY: 74460

African (AFR) AF: 0.104 AC: 4310 AN: 41546

American (AMR) AF: 0.0611 AC: 934 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0542 AC: 188 AN: 3470

East Asian (EAS) AF: 0.0855 AC: 444 AN: 5192

South Asian (SAS) AF: 0.119 AC: 574 AN: 4832

European-Finnish (FIN) AF: 0.0525 AC: 557 AN: 10610

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0224 AC: 1527 AN: 68032

Other (OTH) AF: 0.0643 AC: 136 AN: 2114

Alfa AF: 0.0455 Hom.: 35

Bravo AF: 0.0591

Asia WGS AF: 0.108 AC: 377 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.5
DANN	Benign	0.34
PhyloP100		0.35
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: rs10492975; hg19: chr1-11235476;