1-11129799-C-T

Variant names:

• chr1-11129799-C-T
• rs139043855
• NM_004958.4:c.5653G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 2P and 18B. PM1 BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_004958.4(MTOR):​c.5653G>A​(p.Val1885Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000304 in 1,614,172 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1885F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (2 hom.)
• Consequence: MTOR NM_004958.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:6
• Conservation: PhyloP100: 7.54
• Publications: 5 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 -16 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 6 uncertain in NM_004958.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.19376647).
• BP6: Variant 1-11129799-C-T is Benign according to our data. Variant chr1-11129799-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 408296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000315 (48/152326) while in subpopulation NFE AF = 0.000515 (35/68022). AF 95% confidence interval is 0.00038. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 48 AD gene.

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.5653G>A	p.Val1885Ile	missense	Exon 40 of 58	NP_004949.1	P42345
	MTOR	NM_001386500.1		c.5653G>A	p.Val1885Ile	missense	Exon 40 of 58	NP_001373429.1	P42345
	MTOR	NM_001386501.1		c.4405G>A	p.Val1469Ile	missense	Exon 39 of 57	NP_001373430.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTOR	ENST00000361445.9	TSL:1 MANE Select	c.5653G>A	p.Val1885Ile	missense	Exon 40 of 58	ENSP00000354558.4	P42345
	MTOR	ENST00000934315.1		c.5707G>A	p.Val1903Ile	missense	Exon 40 of 58	ENSP00000604374.1
	MTOR	ENST00000934312.1		c.5674G>A	p.Val1892Ile	missense	Exon 40 of 58	ENSP00000604371.1

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000342 AC: 86 AN: 251424 AF XY: 0.000353

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000528

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000302 AC: 442 AN: 1461846 Hom.: 2 Cov.: 30 AF XY: 0.000272 AC XY: 198 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000765 AC: 20 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86254

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53414

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.000324 AC: 360 AN: 1111980

Other (OTH) AF: 0.000447 AC: 27 AN: 60396

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74478

African (AFR) AF: 0.0000722 AC: 3 AN: 41574

American (AMR) AF: 0.000392 AC: 6 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000564 Hom.: 0

Bravo AF: 0.000302

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000346 AC: 42

EpiCase AF: 0.000600

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	1	-	Isolated focal cortical dysplasia type II;C4225259:Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome (1)
-	-	1	MTOR-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.0	L
PhyloP100		7.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.86	N
REVEL	Uncertain	0.32
Sift	Benign	0.66	T
Sift4G	Benign	0.78	T
Polyphen		0.98	D
Vest4		0.52
MVP		0.76
MPC		1.0
ClinPred		0.052	T
GERP RS		5.8
Varity_R		0.14
gMVP		0.54
Mutation Taster		=36/64	disease causing

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: rs139043855; hg19: chr1-11189856; COSMIC: COSV106109645; COSMIC: COSV106109645;