chr1-11144645-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004958.4(MTOR):​c.4872+3G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

MTOR
NM_004958.4 splice_region, intron

Scores

2
Splicing: ADA: 0.2885
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.439
Variant links:
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-AS1 (HGNC:40242): (MTOR antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.41).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MTORNM_004958.4 linkc.4872+3G>C splice_region_variant, intron_variant Intron 34 of 57 ENST00000361445.9 NP_004949.1 P42345

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MTORENST00000361445.9 linkc.4872+3G>C splice_region_variant, intron_variant Intron 34 of 57 1 NM_004958.4 ENSP00000354558.4 P42345

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Jan 11, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change falls in intron 34 of the MTOR gene. It does not directly change the encoded amino acid sequence of the MTOR protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MTOR-related conditions. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.41
CADD
Benign
17
DANN
Benign
0.82
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
3.0

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.29
dbscSNV1_RF
Benign
0.59
SpliceAI score (max)
0.26
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.26
Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-11204702; API