rs796053452

Variant names:

• chr9-132928784-T-C
• rs796053452
• NM_000368.5:c.89A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_000368.5(TSC1):​c.89A>G​(p.Lys30Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K30K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 2.22
• 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: Ambry Genetics, PanelApp Australia, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23860356).
• BP6: Variant 9-132928784-T-C is Benign according to our data. Variant chr9-132928784-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 207623.
• BS2: High AC in GnomAdExome4 at 72 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.89A>G	p.Lys30Arg	missense	Exon 3 of 23	NP_000359.1
	TSC1	NM_001406592.1		c.89A>G	p.Lys30Arg	missense	Exon 3 of 23	NP_001393521.1
	TSC1	NM_001406593.1		c.89A>G	p.Lys30Arg	missense	Exon 3 of 23	NP_001393522.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	ENST00000298552.9	TSL:1 MANE Select	c.89A>G	p.Lys30Arg	missense	Exon 3 of 23	ENSP00000298552.3
	TSC1	ENST00000490179.4	TSL:3	c.89A>G	p.Lys30Arg	missense	Exon 4 of 24	ENSP00000495533.2
	TSC1	ENST00000403810.6	TSL:1	c.89A>G	p.Lys30Arg	missense	Exon 3 of 10	ENSP00000386093.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000493 AC: 72 AN: 1461834 Hom.: 0 Cov.: 31 AF XY: 0.0000426 AC XY: 31 AN XY: 727226

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000603 AC: 67 AN: 1111982

Other (OTH) AF: 0.0000828 AC: 5 AN: 60388

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74382

African (AFR) AF: 0.0000241 AC: 1 AN: 41470

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000679 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	2	Tuberous sclerosis 1 (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	TSC1-related disorder (1)
-	1	-	Tuberous sclerosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.055
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	-0.039	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.2
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.23
Sift	Benign	0.35	T
Sift4G	Benign	0.68	T
Polyphen		0.23	B
Vest4		0.19
MutPred		0.62		Loss of ubiquitination at K30 (P = 0.0092)
MVP		0.82
MPC		0.42
ClinPred		0.50	D
GERP RS		3.9
PromoterAI		-0.00080	Neutral
Varity_R		0.063
gMVP		0.11
Mutation Taster		=97/3	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: rs796053452; hg19: chr9-135804171;