chr1-11212805-G-C

Variant names:

• chr1-11212805-G-C
• rs371126703
• NM_004958.4:c.3389C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_004958.4(MTOR):​c.3389C>G​(p.Pro1130Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1130L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MTOR NM_004958.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.58

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.117607474).
• BP6: Variant 1-11212805-G-C is Benign according to our data. Variant chr1-11212805-G-C is described in ClinVar as [Benign]. Clinvar id is 1008250.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTOR	NM_004958.4	c.3389C>G	p.Pro1130Arg	missense_variant	Exon 22 of 58	ENST00000361445.9	NP_004949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTOR	ENST00000361445.9	c.3389C>G	p.Pro1130Arg	missense_variant	Exon 22 of 58	1	NM_004958.4	ENSP00000354558.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460508 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726632

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Benign	0.69
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.073
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.060
Sift	Benign	0.67	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.24
MutPred		0.28		Loss of glycosylation at P1130 (P = 0.0199);
MVP		0.51
MPC		0.86
ClinPred		0.30	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.056
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs371126703; hg19: chr1-11272862;