rs45468995

Variant names:

• chr9-132897294-G-A
• rs45468995
• NM_000368.5:c.2865C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-132897294-G-A
• chr9-132897294-G-T

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.2865C>T​(p.Thr955Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,614,154 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (8 hom.)
• Consequence: TSC1 NM_000368.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25 O:1
• Conservation: PhyloP100: -0.260
• Publications: 8 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=-0.46).
• BP6: Variant 9-132897294-G-A is Benign according to our data. Variant chr9-132897294-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 49008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.26 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00187 (284/152264) while in subpopulation NFE AF = 0.00356 (242/68022). AF 95% confidence interval is 0.00319. There are 2 homozygotes in GnomAd4. There are 128 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 284 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.2865C>T	p.Thr955Thr	synonymous	Exon 22 of 23	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.2865C>T	p.Thr955Thr	synonymous	Exon 22 of 23	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.2865C>T	p.Thr955Thr	synonymous	Exon 22 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.2865C>T	p.Thr955Thr	synonymous	Exon 22 of 23	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.2865C>T	p.Thr955Thr	synonymous	Exon 23 of 24	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000643875.1		c.2865C>T	p.Thr955Thr	synonymous	Exon 22 of 23	ENSP00000495158.1	Q92574-1

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 284 AN: 152146 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00356

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00161 AC: 405 AN: 251496 AF XY: 0.00157

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00272

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.00259 AC: 3792 AN: 1461890 Hom.: 8 Cov.: 33 AF XY: 0.00253 AC XY: 1842 AN XY: 727248

African (AFR) AF: 0.000627 AC: 21 AN: 33480

American (AMR) AF: 0.00101 AC: 45 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

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

South Asian (SAS) AF: 0.00119 AC: 103 AN: 86258

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00314 AC: 3488 AN: 1112012

Other (OTH) AF: 0.00210 AC: 127 AN: 60396

GnomAD4 genome AF: 0.00187 AC: 284 AN: 152264 Hom.: 2 Cov.: 32 AF XY: 0.00172 AC XY: 128 AN XY: 74458

African (AFR) AF: 0.000506 AC: 21 AN: 41530

American (AMR) AF: 0.000980 AC: 15 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00356 AC: 242 AN: 68022

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00256 Hom.: 0

Bravo AF: 0.00192

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00172

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	6	Tuberous sclerosis 1 (6)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1854465:Tuberous sclerosis 1 (2)
-	-	2	not provided (2)
-	-	2	Tuberous sclerosis syndrome (3)
-	-	1	Isolated focal cortical dysplasia type II (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	5.5
DANN	Benign	0.67
PhyloP100		-0.26
Mutation Taster		=100/0	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: rs45468995; hg19: chr9-135772681; COSMIC: COSV104404429; COSMIC: COSV104404429;