rs56051835

chr1-11124536-A-Gchr1-11124536-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004958.4(MTOR):c.6624T>C(p.Leu2208=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00296 in 1,611,314 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (56 hom.)
• Consequence: MTOR NM_004958.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.198

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 1-11124536-A-G is Benign according to our data. Variant chr1-11124536-A-G is described in ClinVar as [Benign]. Clinvar id is 414895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11124536-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.198 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00303 (462/152326) while in subpopulation SAS AF= 0.0149 (72/4818). AF 95% confidence interval is 0.0122. There are 9 homozygotes in gnomad4. There are 248 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 463 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTOR	NM_004958.4	c.6624T>C	p.Leu2208=	synonymous_variant	47/58	ENST00000361445.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTOR	ENST00000361445.9	c.6624T>C	p.Leu2208=	synonymous_variant	47/58	1	NM_004958.4	P1

Frequencies

GnomAD3 genomes AF: 0.00304 AC: 463 AN: 152208 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.0446

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0149

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00212

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00499 AC: 1256 AN: 251458 Hom.: 21 AF XY: 0.00551 AC XY: 749 AN XY: 135904

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.0444

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0120

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00302

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00295 AC: 4309 AN: 1458988 Hom.: 56 Cov.: 31 AF XY: 0.00335 AC XY: 2432 AN XY: 725052

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.0440

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.0126

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.00142

Gnomad4 OTH exome AF: 0.00554

GnomAD4 genome AF: 0.00303 AC: 462 AN: 152326 Hom.: 9 Cov.: 32 AF XY: 0.00333 AC XY: 248 AN XY: 74482

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.0446

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0149

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00212

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00557 Hom.: 8

Bravo AF: 0.00297

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.00436

EpiControl AF: 0.00445

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	MTOR: BP4, BP7, BS1, BS2 -

Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	2.3
Dann	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs56051835; hg19: chr1-11184593; COSMIC: COSV63879465;