NM_000368.5:c.1579C>G

Variant names:

• chr9-132905999-G-C
• rs118203549
• NM_000368.5:c.1579C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000368.5(TSC1):​c.1579C>G​(p.Gln527Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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. Q527R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.06
• 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 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 10 benign, 15 uncertain in NM_000368.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29122144).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.1579C>G	p.Gln527Glu	missense_variant	Exon 15 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.1579C>G	p.Gln527Glu	missense_variant	Exon 15 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.1579C>G	p.Gln527Glu	missense_variant	Exon 16 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.44	T;.;T;.;.;T;.;T;.;.;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.78	.;T;T;T;T;.;.;.;T;T;.
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.29	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.2	M;.;M;.;.;M;.;M;.;.;.
PhyloP100		6.1
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.55	N;N;N;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.36
Sift	Benign	0.059	T;T;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.71	T;T;T;.;.;.;.;.;.;.;.
Polyphen		0.82	P;.;P;.;.;P;.;P;.;.;.
Vest4		0.60
MutPred		0.46		Gain of phosphorylation at S530 (P = 0.1359);.;Gain of phosphorylation at S530 (P = 0.1359);.;.;Gain of phosphorylation at S530 (P = 0.1359);.;Gain of phosphorylation at S530 (P = 0.1359);.;Gain of phosphorylation at S530 (P = 0.1359);.;
MVP		0.83
MPC		0.66
ClinPred		0.89	D
GERP RS		5.1
Varity_R		0.073
gMVP		0.27
Mutation Taster		=95/5	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: rs118203549; hg19: chr9-135781386; COSMIC: COSV53771148;