rs571156267

Variant names:

• chr1-11130640-CGTGGTGGCGGCA-C
• rs571156267
• NM_004958.4:c.5490_5501delTGCCGCCACCAC

Your query was ambiguous. Multiple possible variants found:

• chr1-11130640-CGTGGTGGCGGCA-C
• chr1-11130640-CGTGGTGGCGGCA-CGTGGTGGCGGCAGTGGTGGCGGCA

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BS1 BS2

The NM_004958.4(MTOR):​c.5490_5501delTGCCGCCACCAC​(p.Ala1831_Thr1834del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000646 in 1,613,568 control chromosomes in the GnomAD database, including 5 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1830T) has been classified as Likely benign. The gene MTOR is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00059 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (4 hom.)
• Consequence: MTOR NM_004958.4 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.78
• Publications: 2 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: G2P, Orphanet, Illumina, Labcorp Genetics (formerly Invitae)
• overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Specifications for MTOR are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -14 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_004958.4.
• BP6: Variant 1-11130640-CGTGGTGGCGGCA-C is Benign according to our data. Variant chr1-11130640-CGTGGTGGCGGCA-C is described in ClinVar as Benign. ClinVar VariationId is 414898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000585 (89/152044) while in subpopulation EAS AF = 0.00775 (40/5160). AF 95% confidence interval is 0.00585. There are 1 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 89 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.5490_5501delTGCCGCCACCAC	p.Ala1831_Thr1834del	disruptive_inframe_deletion	Exon 39 of 58	NP_004949.1	P42345
	MTOR	NM_001386500.1		c.5490_5501delTGCCGCCACCAC	p.Ala1831_Thr1834del	disruptive_inframe_deletion	Exon 39 of 58	NP_001373429.1	P42345
	MTOR	NM_001386501.1		c.4242_4253delTGCCGCCACCAC	p.Ala1415_Thr1418del	disruptive_inframe_deletion	Exon 38 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.5490_5501delTGCCGCCACCAC	p.Ala1831_Thr1834del	disruptive_inframe_deletion	Exon 39 of 58	ENSP00000354558.4	P42345
	MTOR	ENST00000934315.1		c.5544_5555delTGCCGCCACCAC	p.Ala1849_Thr1852del	disruptive_inframe_deletion	Exon 39 of 58	ENSP00000604374.1
	MTOR	ENST00000934312.1		c.5511_5522delTGCCGCCACCAC	p.Ala1838_Thr1841del	disruptive_inframe_deletion	Exon 39 of 58	ENSP00000604371.1

Frequencies

GnomAD3 genomes AF: 0.000586 AC: 89 AN: 151926 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00773

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000589

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.00111 AC: 275 AN: 247814 AF XY: 0.00110

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0107

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000506

Gnomad OTH exome AF: 0.000657

GnomAD4 exome AF: 0.000652 AC: 953 AN: 1461524 Hom.: 4 AF XY: 0.000686 AC XY: 499 AN XY: 727062

African (AFR) AF: 0.000209 AC: 7 AN: 33468

American (AMR) AF: 0.0000895 AC: 4 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00504 AC: 200 AN: 39700

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86176

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53376

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.000592 AC: 658 AN: 1111874

Other (OTH) AF: 0.000745 AC: 45 AN: 60376

GnomAD4 genome AF: 0.000585 AC: 89 AN: 152044 Hom.: 1 Cov.: 32 AF XY: 0.000552 AC XY: 41 AN XY: 74334

African (AFR) AF: 0.0000723 AC: 3 AN: 41492

American (AMR) AF: 0.000131 AC: 2 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00775 AC: 40 AN: 5160

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4798

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000589 AC: 40 AN: 67948

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.000400 Hom.: 0

Bravo AF: 0.000778

EpiCase AF: 0.000600

EpiControl AF: 0.000653

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.8
Mutation Taster		=176/24	polymorphism

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs571156267;

hg19: chr1-11190697;

COSMIC: COSV63868577;

COSMIC: COSV63868577;