chr9-132902711-T-A

Position:

• chr9-132902711-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000368.5(TSC1):​c.2285A>T​(p.Asn762Ile) 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 benign outcome for this variant. 14/21 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. N762S) 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: 1.09

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13408652).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2285A>T	p.Asn762Ile	missense_variant	18/23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.2285A>T	p.Asn762Ile	missense_variant	18/23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.2285A>T	p.Asn762Ile	missense_variant	19/24	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	Benign	0.094
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.55	D;.;D;.;.;D;.;D;.;.;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.85	.;T;D;T;T;.;.;.;D;D;.
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.69	N;.;N;.;.;N;.;N;.;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.9	N;N;N;.;.;.;.;.;.;.;.
REVEL	Benign	0.21
Sift	Benign	0.19	T;T;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.20	T;T;T;.;.;.;.;.;.;.;.
Polyphen		0.070	B;.;B;.;.;B;.;B;.;.;.
Vest4		0.41
MutPred		0.26		Gain of MoRF binding (P = 0.0825);.;Gain of MoRF binding (P = 0.0825);.;.;Gain of MoRF binding (P = 0.0825);.;Gain of MoRF binding (P = 0.0825);.;.;.;
MVP		0.40
MPC		0.63
ClinPred		0.51	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.11

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-135778098;