rs118203576

Variant names:

• chr9-132905818-T-C
• rs118203576
• NM_000368.5:c.1760A>G

Your query was ambiguous. Multiple possible variants found:

• chr9-132905818-T-C
• chr9-132905818-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000368.5(TSC1):​c.1760A>G​(p.Lys587Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00671 in 1,614,146 control chromosomes in the GnomAD database, including 890 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K587E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (138 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (752 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:26 O:2
• Conservation: PhyloP100: 4.50
• Publications: 25 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017258227).
• BP6: Variant 9-132905818-T-C is Benign according to our data. Variant chr9-132905818-T-C is described in ClinVar as Benign. ClinVar VariationId is 5099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

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.1760A>G	p.Lys587Arg	missense	Exon 15 of 23	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.1760A>G	p.Lys587Arg	missense	Exon 15 of 23	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.1760A>G	p.Lys587Arg	missense	Exon 15 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.1760A>G	p.Lys587Arg	missense	Exon 15 of 23	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.1760A>G	p.Lys587Arg	missense	Exon 16 of 24	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000643875.1		c.1760A>G	p.Lys587Arg	missense	Exon 15 of 23	ENSP00000495158.1	Q92574-1

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2052 AN: 152150 Hom.: 136 Cov.: 32

Gnomad AFR AF: 0.00236

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.0260 AC: 6526 AN: 251104 AF XY: 0.0198

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0120

Gnomad NFE exome AF: 0.000467

Gnomad OTH exome AF: 0.0204

GnomAD4 exome AF: 0.00600 AC: 8768 AN: 1461878 Hom.: 752 Cov.: 31 AF XY: 0.00515 AC XY: 3743 AN XY: 727238

African (AFR) AF: 0.00158 AC: 53 AN: 33480

American (AMR) AF: 0.168 AC: 7511 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.000522 AC: 45 AN: 86256

European-Finnish (FIN) AF: 0.0110 AC: 586 AN: 53414

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.000180 AC: 200 AN: 1112006

Other (OTH) AF: 0.00599 AC: 362 AN: 60396

GnomAD4 genome AF: 0.0135 AC: 2062 AN: 152268 Hom.: 138 Cov.: 32 AF XY: 0.0153 AC XY: 1137 AN XY: 74450

African (AFR) AF: 0.00236 AC: 98 AN: 41564

American (AMR) AF: 0.115 AC: 1761 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.0118 AC: 125 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000573 AC: 39 AN: 68016

Other (OTH) AF: 0.0171 AC: 36 AN: 2110

Alfa AF: 0.00493 Hom.: 108

Bravo AF: 0.0210

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0188 AC: 2278

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (11)
-	1	7	Tuberous sclerosis 1 (8)
-	-	4	not provided (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Isolated focal cortical dysplasia type II (1)
-	-	1	Lung lymphangioleiomyomatosis (1)
-	-	1	Tuberous sclerosis syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.42	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.24
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.5	L
PhyloP100		4.5
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.25
Sift	Benign	0.045	D
Sift4G	Benign	0.59	T
Polyphen		0.010	B
Vest4		0.23
MPC		0.49
ClinPred		0.016	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.059
gMVP		0.17
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs118203576; hg19: chr9-135781205; COSMIC: COSV53769494; COSMIC: COSV53769494;