NM_000368.5:c.3282G>A

Variant names:

• chr9-132896448-C-T
• rs116747861
• NM_000368.5:c.3282G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000368.5(TSC1):​c.3282G>A​(p.Glu1094Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,614,220 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (8 hom.)
• Consequence: TSC1 NM_000368.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20 O:1
• Conservation: PhyloP100: 1.60
• Publications: 6 publications found

Genes affected

TSC1 (HGNC:12362): (TSC complex subunit 1) This gene is a tumor suppressor gene that encodes the growth inhibitory protein hamartin. The encoded protein interacts with and stabilizes the GTPase activating protein tuberin. This hamartin-tuberin complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. This protein also functions as a co-chaperone for Hsp90 that inhibits its ATPase activity. This protein functions as a facilitator of Hsp90-mediated folding of kinase and non-kinase clients, including TSC2 and thereby preventing their ubiquitination and proteasomal degradation. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

TSC1 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
• lung lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 9-132896448-C-T is Benign according to our data. Variant chr9-132896448-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 49019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.6 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00427 (650/152326) while in subpopulation AFR AF = 0.0123 (513/41570). AF 95% confidence interval is 0.0115. There are 1 homozygotes in GnomAd4. There are 312 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 650 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000368.5. 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
	TSC1	NM_000368.5	MANE Select	c.3282G>A	p.Glu1094Glu	synonymous	Exon 23 of 23	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.3282G>A	p.Glu1094Glu	synonymous	Exon 23 of 23	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.3282G>A	p.Glu1094Glu	synonymous	Exon 23 of 23	NP_001393522.1	Q92574-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	ENST00000298552.9	TSL:1 MANE Select	c.3282G>A	p.Glu1094Glu	synonymous	Exon 23 of 23	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.3282G>A	p.Glu1094Glu	synonymous	Exon 24 of 24	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000643875.1		c.3282G>A	p.Glu1094Glu	synonymous	Exon 23 of 23	ENSP00000495158.1	Q92574-1

Frequencies

GnomAD3 genomes AF: 0.00426 AC: 649 AN: 152208 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00176 AC: 443 AN: 251462 AF XY: 0.00157

Gnomad AFR exome AF: 0.0140

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.00456

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000668

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00101 AC: 1483 AN: 1461894 Hom.: 8 Cov.: 31 AF XY: 0.00100 AC XY: 729 AN XY: 727248

African (AFR) AF: 0.0148 AC: 497 AN: 33480

American (AMR) AF: 0.00212 AC: 95 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00467 AC: 122 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53420

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5768

European-Non Finnish (NFE) AF: 0.000527 AC: 586 AN: 1112012

Other (OTH) AF: 0.00248 AC: 150 AN: 60396

GnomAD4 genome AF: 0.00427 AC: 650 AN: 152326 Hom.: 1 Cov.: 32 AF XY: 0.00419 AC XY: 312 AN XY: 74496

African (AFR) AF: 0.0123 AC: 513 AN: 41570

American (AMR) AF: 0.00418 AC: 64 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 68026

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00208 Hom.: 2

Bravo AF: 0.00505

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00107

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	6	Tuberous sclerosis 1 (6)
-	-	4	not provided (4)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Isolated focal cortical dysplasia type II (1)
-	-	1	Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1854465:Tuberous sclerosis 1 (1)
-	-	1	Tuberous sclerosis syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	8.3
DANN	Benign	0.51
PhyloP100		1.6
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs116747861; hg19: chr9-135771835;