9-132903782-C-T

Variant names:

• chr9-132903782-C-T
• NM_000368.5:c.2077G>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.2077G>A​(p.Asp693Asn) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D693H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.14

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=0.16548443).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2077G>A	p.Asp693Asn	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.2077G>A	p.Asp693Asn	missense_variant	Exon 17 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.2077G>A	p.Asp693Asn	missense_variant	Exon 18 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Isolated focal cortical dysplasia type II Uncertain:1

Oct 10, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tuberous sclerosis 1 Uncertain:1

Feb 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with TSC1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 693 of the TSC1 protein (p.Asp693Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Benign	0.39	T;.;T;.;.;T;.;T;.;.;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.89	.;D;D;D;D;.;.;.;D;D;.
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	-1.1	N;.;N;.;.;N;.;N;.;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.76	N;N;N;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.36
Sift	Benign	0.89	T;T;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.78	T;T;T;.;.;.;.;.;.;.;.
Polyphen		0.0020	B;.;B;.;.;B;.;B;.;.;.
Vest4		0.20
MutPred		0.58		Gain of MoRF binding (P = 0.0706);.;Gain of MoRF binding (P = 0.0706);.;.;Gain of MoRF binding (P = 0.0706);.;Gain of MoRF binding (P = 0.0706);.;.;.;
MVP		0.50
MPC		0.49
ClinPred		0.87	D
GERP RS		4.3
Varity_R		0.057
gMVP		0.13

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: chr9-135779169;