rs35903812

Variant names:

• chr1-11247950-C-T
• rs35903812
• NM_004958.4:c.985G>A

Variant summary

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

The NM_004958.4(MTOR):​c.985G>A​(p.Ala329Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00338 in 1,614,150 control chromosomes in the GnomAD database, including 9 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. A329S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (8 hom.)
• Consequence: MTOR NM_004958.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 7.54
• Publications: 11 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013919532).
• BP6: Variant 1-11247950-C-T is Benign according to our data. Variant chr1-11247950-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 414904.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 = 0.00258 (393/152256) while in subpopulation NFE AF = 0.00426 (290/68018). AF 95% confidence interval is 0.00386. There are 1 homozygotes in GnomAd4. There are 158 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 393 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.985G>A	p.Ala329Thr	missense	Exon 7 of 58	NP_004949.1	P42345
	MTOR	NM_001386500.1		c.985G>A	p.Ala329Thr	missense	Exon 7 of 58	NP_001373429.1	P42345
	MTOR	NM_001386501.1		c.-155G>A		5_prime_UTR	Exon 7 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.985G>A	p.Ala329Thr	missense	Exon 7 of 58	ENSP00000354558.4	P42345
	MTOR	ENST00000934315.1		c.985G>A	p.Ala329Thr	missense	Exon 7 of 58	ENSP00000604374.1
	MTOR	ENST00000934312.1		c.985G>A	p.Ala329Thr	missense	Exon 7 of 58	ENSP00000604371.1

Frequencies

GnomAD3 genomes AF: 0.00260 AC: 395 AN: 152138 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00328

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00426

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00264 AC: 665 AN: 251438 AF XY: 0.00267

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.00416

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00347 AC: 5070 AN: 1461894 Hom.: 8 Cov.: 32 AF XY: 0.00347 AC XY: 2527 AN XY: 727248

African (AFR) AF: 0.000896 AC: 30 AN: 33480

American (AMR) AF: 0.00282 AC: 126 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00249 AC: 65 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000997 AC: 86 AN: 86258

European-Finnish (FIN) AF: 0.000431 AC: 23 AN: 53420

Middle Eastern (MID) AF: 0.0114 AC: 66 AN: 5768

European-Non Finnish (NFE) AF: 0.00402 AC: 4473 AN: 1112012

Other (OTH) AF: 0.00333 AC: 201 AN: 60396

GnomAD4 genome AF: 0.00258 AC: 393 AN: 152256 Hom.: 1 Cov.: 32 AF XY: 0.00212 AC XY: 158 AN XY: 74454

African (AFR) AF: 0.000650 AC: 27 AN: 41554

American (AMR) AF: 0.00327 AC: 50 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

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

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00426 AC: 290 AN: 68018

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00360 Hom.: 0

Bravo AF: 0.00280

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00453 AC: 39

ExAC AF: 0.00268 AC: 326

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00518

EpiControl AF: 0.00415

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not provided (8)
-	-	1	MTOR-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.2	L
PhyloP100		7.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.19
Sift	Benign	0.48	T
Sift4G	Benign	0.59	T
Polyphen		0.28	B
Vest4		0.77
MVP		0.77
MPC		0.83
ClinPred		0.021	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.46
Mutation Taster		=79/21	polymorphism

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: rs35903812; hg19: chr1-11308007; COSMIC: COSV63870597;