rs55774271

Variant names:

• chr1-11139391-C-T
• rs55774271
• NM_004958.4:c.5043G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-11139391-C-T
• chr1-11139391-C-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004958.4(MTOR):​c.5043G>A​(p.Pro1681Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,613,860 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (36 hom.)
• Consequence: MTOR NM_004958.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.04
• Publications: 3 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 1-11139391-C-T is Benign according to our data. Variant chr1-11139391-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 414909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.04 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0105 (1602/152238) while in subpopulation AFR AF = 0.036 (1494/41532). AF 95% confidence interval is 0.0345. There are 21 homozygotes in GnomAd4. There are 764 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1602 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.5043G>A	p.Pro1681Pro	synonymous	Exon 36 of 58	NP_004949.1	P42345
	MTOR	NM_001386500.1		c.5043G>A	p.Pro1681Pro	synonymous	Exon 36 of 58	NP_001373429.1	P42345
	MTOR	NM_001386501.1		c.3795G>A	p.Pro1265Pro	synonymous	Exon 35 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.5043G>A	p.Pro1681Pro	synonymous	Exon 36 of 58	ENSP00000354558.4	P42345
	MTOR	ENST00000934315.1		c.5097G>A	p.Pro1699Pro	synonymous	Exon 36 of 58	ENSP00000604374.1
	MTOR	ENST00000934312.1		c.5064G>A	p.Pro1688Pro	synonymous	Exon 36 of 58	ENSP00000604371.1

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1601 AN: 152120 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0361

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00400

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00283 AC: 711 AN: 251086 AF XY: 0.00203

Gnomad AFR exome AF: 0.0358

Gnomad AMR exome AF: 0.00169

Gnomad ASJ exome AF: 0.00338

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00132 AC: 1936 AN: 1461622 Hom.: 36 Cov.: 30 AF XY: 0.00113 AC XY: 820 AN XY: 727140

African (AFR) AF: 0.0411 AC: 1374 AN: 33446

American (AMR) AF: 0.00193 AC: 86 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.00306 AC: 80 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.000183 AC: 203 AN: 1111952

Other (OTH) AF: 0.00293 AC: 177 AN: 60372

GnomAD4 genome AF: 0.0105 AC: 1602 AN: 152238 Hom.: 21 Cov.: 32 AF XY: 0.0103 AC XY: 764 AN XY: 74424

African (AFR) AF: 0.0360 AC: 1494 AN: 41532

American (AMR) AF: 0.00399 AC: 61 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68018

Other (OTH) AF: 0.00427 AC: 9 AN: 2108

Alfa AF: 0.00580 Hom.: 9

Bravo AF: 0.0117

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	2.1
DANN	Benign	0.75
PhyloP100		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs55774271; hg19: chr1-11199448; COSMIC: COSV63879011;