rs142662480

Variant names:

• chr9-132903744-C-A
• rs142662480
• NM_000368.5:c.2115G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-132903744-C-A
• chr9-132903744-C-G
• chr9-132903744-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000368.5(TSC1):​c.2115G>T​(p.Glu705Asp) variant causes a missense change involving the alteration of a non-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. Synonymous variant affecting the same amino acid position (i.e. E705E) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.38
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2115G>T	p.Glu705Asp	missense_variant	Exon 17 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.2115G>T	p.Glu705Asp	missense_variant	Exon 17 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.2115G>T	p.Glu705Asp	missense_variant	Exon 18 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.;D;.;.;D;.;D;.;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	.;D;D;D;D;.;.;.;D;D;.
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.5	M;.;M;.;.;M;.;M;.;.;.
PhyloP100		1.4
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.9	D;D;D;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;D;.;.;.;.;.;.;.;.
Sift4G	Benign	0.076	T;T;T;.;.;.;.;.;.;.;.
Polyphen		1.0	D;.;D;.;.;D;.;D;.;.;.
Vest4		0.84
MutPred		0.76		Gain of MoRF binding (P = 0.1117);.;Gain of MoRF binding (P = 0.1117);.;.;Gain of MoRF binding (P = 0.1117);.;Gain of MoRF binding (P = 0.1117);.;.;.;
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.75
gMVP		0.68
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs142662480; hg19: chr9-135779131;