9-132911509-G-T

Variant names:

• chr9-132911509-G-T
• rs118203474
• NM_000368.5:c.973C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000368.5(TSC1):​c.973C>A​(p.Gln325Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q325E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.17
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.973C>A	p.Gln325Lys	missense_variant	Exon 10 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.973C>A	p.Gln325Lys	missense_variant	Exon 10 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.973C>A	p.Gln325Lys	missense_variant	Exon 11 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461866 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727238

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: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.;T;.;T;.;T;.;.;.;.;.;.;.;.;.;.;T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	.;T;T;T;.;.;.;T;T;.;T;.;.;T;T;T;T;T
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.3	M;.;M;.;M;.;M;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		6.2
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.53	N;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N
REVEL	Uncertain	0.56
Sift	Benign	0.75	T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T
Sift4G	Benign	0.17	T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T
Polyphen		0.81	P;.;P;.;P;.;P;.;.;.;.;D;D;D;.;.;.;P
Vest4		0.55
MutPred		0.49		Gain of ubiquitination at Q325 (P = 0.0094);.;Gain of ubiquitination at Q325 (P = 0.0094);Gain of ubiquitination at Q325 (P = 0.0094);Gain of ubiquitination at Q325 (P = 0.0094);Gain of ubiquitination at Q325 (P = 0.0094);Gain of ubiquitination at Q325 (P = 0.0094);Gain of ubiquitination at Q325 (P = 0.0094);Gain of ubiquitination at Q325 (P = 0.0094);.;.;Gain of ubiquitination at Q325 (P = 0.0094);Gain of ubiquitination at Q325 (P = 0.0094);Gain of ubiquitination at Q325 (P = 0.0094);Gain of ubiquitination at Q325 (P = 0.0094);Gain of ubiquitination at Q325 (P = 0.0094);.;Gain of ubiquitination at Q325 (P = 0.0094);
MVP		0.86
MPC		0.82
ClinPred		0.62	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.38
Mutation Taster		=83/17	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: rs118203474; hg19: chr9-135786896; COSMIC: COSV53768622; COSMIC: COSV53768622;