9-132921835-A-T

Position:

• chr9-132921835-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001406626.1(TSC1):​c.-231T>A variant causes a 5 prime UTR premature start codon gain 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_001406626.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.647T>A	p.Phe216Tyr	missense_variant	7/23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.647T>A	p.Phe216Tyr	missense_variant	7/23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.647T>A	p.Phe216Tyr	missense_variant	8/24	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	0.66
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;.;D;.;D;.;D;.;.;.;.;.;.;.;.;.;.;D;.;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	.;D;D;D;.;.;.;D;D;.;D;.;.;D;D;D;D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.5	M;.;M;.;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.5	N;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Polyphen		0.99	D;.;D;.;D;.;D;.;.;.;.;D;D;D;.;.;.;D;.;.
Vest4		0.88
MutPred		0.71		Gain of phosphorylation at F216 (P = 0.0311);.;Gain of phosphorylation at F216 (P = 0.0311);Gain of phosphorylation at F216 (P = 0.0311);Gain of phosphorylation at F216 (P = 0.0311);Gain of phosphorylation at F216 (P = 0.0311);Gain of phosphorylation at F216 (P = 0.0311);Gain of phosphorylation at F216 (P = 0.0311);Gain of phosphorylation at F216 (P = 0.0311);.;.;Gain of phosphorylation at F216 (P = 0.0311);Gain of phosphorylation at F216 (P = 0.0311);Gain of phosphorylation at F216 (P = 0.0311);Gain of phosphorylation at F216 (P = 0.0311);Gain of phosphorylation at F216 (P = 0.0311);.;Gain of phosphorylation at F216 (P = 0.0311);.;Gain of phosphorylation at F216 (P = 0.0311);
MVP		0.94
MPC		1.5
ClinPred		0.98	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66
gMVP		0.62

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-135797222;