9-132925642-C-G

Variant names:

• chr9-132925642-C-G
• rs118203364
• NM_000368.5:c.308G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000368.5(TSC1):​c.308G>C​(p.Trp103Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. W103L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.71
• Publications: 1 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.308G>C	p.Trp103Ser	missense_variant	Exon 5 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.308G>C	p.Trp103Ser	missense_variant	Exon 5 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.308G>C	p.Trp103Ser	missense_variant	Exon 6 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D;D;.;D;.;D;.;.;.;.;.;.;.;D;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	.;D;D;.;.;.;D;D;.;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.5	M;M;.;M;.;M;.;.;.;.;.;.;.;.;.;.
PhyloP100		7.7
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-11	D;D;.;.;.;.;.;.;.;.;.;.;.;D;.;.
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Sift4G	Pathogenic	0.0	D;D;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Polyphen		1.0	D;D;.;D;.;D;.;.;D;D;D;.;.;D;.;.
Vest4		0.88
MutPred		0.81		Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);
MVP		0.94
MPC		1.8
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.98
gMVP		0.71
Mutation Taster		=12/88	disease causing

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: rs118203364; hg19: chr9-135801029;