rs28730694

Variant names:

• chr1-11248017-G-A
• rs28730694
• NM_004958.4:c.918C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001386501.1(MTOR):​c.-222C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,614,090 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (36 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (26 hom.)
• Consequence: MTOR NM_001386501.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.573
• Publications: 2 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=-0.69).
• BP6: Variant 1-11248017-G-A is Benign according to our data. Variant chr1-11248017-G-A is described in ClinVar as Benign. ClinVar VariationId is 414908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0105 (1597/152234) while in subpopulation AFR AF = 0.0373 (1548/41534). AF 95% confidence interval is 0.0357. There are 36 homozygotes in GnomAd4. There are 746 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1597 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386501.1. 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.918C>T	p.Phe306Phe	synonymous	Exon 7 of 58	NP_004949.1
	MTOR	NM_001386501.1		c.-222C>T		5_prime_UTR_premature_start_codon_gain	Exon 7 of 57	NP_001373430.1
	MTOR	NM_001386500.1		c.918C>T	p.Phe306Phe	synonymous	Exon 7 of 58	NP_001373429.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTOR	ENST00000361445.9	TSL:1 MANE Select	c.918C>T	p.Phe306Phe	synonymous	Exon 7 of 58	ENSP00000354558.4
	MTOR	ENST00000934315.1		c.918C>T	p.Phe306Phe	synonymous	Exon 7 of 58	ENSP00000604374.1
	MTOR	ENST00000934312.1		c.918C>T	p.Phe306Phe	synonymous	Exon 7 of 58	ENSP00000604371.1

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1588 AN: 152116 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0372

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00276 AC: 693 AN: 251022 AF XY: 0.00200

Gnomad AFR exome AF: 0.0383

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.00109 AC: 1600 AN: 1461856 Hom.: 26 Cov.: 32 AF XY: 0.000920 AC XY: 669 AN XY: 727226

African (AFR) AF: 0.0395 AC: 1322 AN: 33480

American (AMR) AF: 0.00170 AC: 76 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53390

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1112006

Other (OTH) AF: 0.00245 AC: 148 AN: 60394

GnomAD4 genome AF: 0.0105 AC: 1597 AN: 152234 Hom.: 36 Cov.: 32 AF XY: 0.0100 AC XY: 746 AN XY: 74432

African (AFR) AF: 0.0373 AC: 1548 AN: 41534

American (AMR) AF: 0.00242 AC: 37 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00582 Hom.: 8

Bravo AF: 0.0119

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.9
DANN	Benign	0.65
PhyloP100		-0.57
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28730694; hg19: chr1-11308074;