9-132905618-G-C

Variant names:

• chr9-132905618-G-C
• rs75820036
• NM_000368.5:c.1960C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000368.5(TSC1):​c.1960C>G​(p.Gln654Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000288 in 1,614,218 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q654K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00041 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (3 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:16 O:1
• Conservation: PhyloP100: 5.59
• Publications: 32 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009436011).
• BP6: Variant 9-132905618-G-C is Benign according to our data. Variant chr9-132905618-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41692.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000407 (62/152342) while in subpopulation EAS AF = 0.00675 (35/5188). AF 95% confidence interval is 0.00499. There are 4 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 62 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.1960C>G	p.Gln654Glu	missense	Exon 15 of 23	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.1960C>G	p.Gln654Glu	missense	Exon 15 of 23	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.1960C>G	p.Gln654Glu	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.1960C>G	p.Gln654Glu	missense	Exon 15 of 23	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.1960C>G	p.Gln654Glu	missense	Exon 16 of 24	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000643875.1		c.1960C>G	p.Gln654Glu	missense	Exon 15 of 23	ENSP00000495158.1	Q92574-1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152224 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00673

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000851 AC: 214 AN: 251330 AF XY: 0.000832

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000276 AC: 403 AN: 1461876 Hom.: 3 Cov.: 31 AF XY: 0.000272 AC XY: 198 AN XY: 727236

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

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

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

East Asian (EAS) AF: 0.00844 AC: 335 AN: 39700

South Asian (SAS) AF: 0.000185 AC: 16 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112012

Other (OTH) AF: 0.000712 AC: 43 AN: 60394

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152342 Hom.: 4 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74494

African (AFR) AF: 0.00 AC: 0 AN: 41586

American (AMR) AF: 0.00157 AC: 24 AN: 15302

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

East Asian (EAS) AF: 0.00675 AC: 35 AN: 5188

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000383 Hom.: 1

Bravo AF: 0.000393

ExAC AF: 0.000824 AC: 100

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	Tuberous sclerosis 1 (6)
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Tuberous sclerosis syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	19
DANN	Benign	0.85
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.31
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0094	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.6
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.030	N
REVEL	Uncertain	0.43
Sift	Benign	0.29	T
Sift4G	Benign	0.22	T
Polyphen		0.0090	B
Vest4		0.52
MVP		0.82
MPC		0.55
ClinPred		0.022	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.091
gMVP		0.52
Mutation Taster		=75/25	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: rs75820036; hg19: chr9-135781005; COSMIC: COSV100052110;