1-11108041-A-G

Position:

• chr1-11108041-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004958.4(MTOR):​c.7634+140T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00264 in 608,670 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (21 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (5 hom.)
• Consequence: MTOR NM_004958.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0570

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-11108041-A-G is Benign according to our data. Variant chr1-11108041-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1218120.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 = 0.00783 (1193/152336) while in subpopulation AFR AF= 0.0267 (1108/41574). AF 95% confidence interval is 0.0253. There are 21 homozygotes in gnomad4. There are 533 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1193 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTOR	NM_004958.4	c.7634+140T>C		intron_variant		ENST00000361445.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTOR	ENST00000361445.9	c.7634+140T>C		intron_variant		1	NM_004958.4	P1

Frequencies

GnomAD3 genomes AF: 0.00776 AC: 1181 AN: 152218 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0264

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00621

GnomAD4 exome AF: 0.000909 AC: 415 AN: 456334 Hom.: 5 AF XY: 0.000810 AC XY: 194 AN XY: 239530

Gnomad4 AFR exome AF: 0.0247

Gnomad4 AMR exome AF: 0.00204

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000470

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000905

Gnomad4 OTH exome AF: 0.00252

GnomAD4 genome AF: 0.00783 AC: 1193 AN: 152336 Hom.: 21 Cov.: 32 AF XY: 0.00715 AC XY: 533 AN XY: 74498

Gnomad4 AFR AF: 0.0267

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00562 Hom.: 1

Bravo AF: 0.00908

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.4
DANN	Benign	0.51

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: rs3730377; hg19: chr1-11168098;