rs76801599

Variant names:

• chr9-132897540-G-A
• rs76801599
• NM_000368.5:c.2696C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-132897540-G-A
• chr9-132897540-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000368.5(TSC1):​c.2696C>T​(p.Thr899Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. T899S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.106
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0920347).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2696C>T	p.Thr899Ile	missense_variant	Exon 21 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.2696C>T	p.Thr899Ile	missense_variant	Exon 21 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.2696C>T	p.Thr899Ile	missense_variant	Exon 22 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449702 Hom.: 0 Cov.: 37 AF XY: 0.00000139 AC XY: 1 AN XY: 721212

African (AFR) AF: 0.00 AC: 0 AN: 33086

American (AMR) AF: 0.00 AC: 0 AN: 44248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25580

East Asian (EAS) AF: 0.00 AC: 0 AN: 38856

South Asian (SAS) AF: 0.00 AC: 0 AN: 85942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104222

Other (OTH) AF: 0.0000168 AC: 1 AN: 59576

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D;.;D;.;.;D;.;D;.;.;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.73
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.85	.;D;D;T;D;.;.;.;D;D;.
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.092	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;N;.;.;N;.;N;.;.;.
PhyloP100		0.11
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.7	D;D;D;.;.;.;.;.;.;.;.
REVEL	Benign	0.17
Sift	Benign	0.080	T;T;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.24	T;T;T;.;.;.;.;.;.;.;.
Polyphen		0.25	B;.;B;.;.;B;.;B;.;.;.
Vest4		0.28
MutPred		0.32		Gain of MoRF binding (P = 0.1441);.;Gain of MoRF binding (P = 0.1441);.;.;Gain of MoRF binding (P = 0.1441);.;Gain of MoRF binding (P = 0.1441);.;.;.;
MVP		0.27
MPC		0.54
ClinPred		0.12	T
GERP RS		-2.6
Varity_R		0.15
gMVP		0.056
Mutation Taster		=90/10	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: rs76801599; hg19: chr9-135772927;