9-132925723-A-T

Position:

• chr9-132925723-A-T

Variant summary

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

The NM_000368.5(TSC1):​c.227T>A​(p.Ile76Asn) variant causes a missense 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 9.10

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.227T>A	p.Ile76Asn	missense_variant	5/23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.227T>A	p.Ile76Asn	missense_variant	5/23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.227T>A	p.Ile76Asn	missense_variant	6/24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 02, 2020

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. This variant has been reported to affect TSC1 protein function (PMID: 21309039). This variant has been observed in individual(s) with tuberous sclerosis complex (PMID: 17304050). ClinVar contains an entry for this variant (Variation ID: 48927). This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with asparagine at codon 76 of the TSC1 protein (p.Ile76Asn). The isoleucine residue is weakly conserved and there is a large physicochemical difference between isoleucine and asparagine. -

Tuberous sclerosis syndrome Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC1)

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D;D;.;D;.;D;.;.;.;.;.;.;.;D;.;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;D;D;.;.;.;D;D;.;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	1.7	L;L;.;L;.;L;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.8	D;D;.;.;.;.;.;.;.;.;.;.;.;D;.;.
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;D;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Sift4G	Uncertain	0.0030	D;D;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Polyphen		0.71	P;P;.;P;.;P;.;.;P;P;P;.;.;P;.;.
Vest4		0.94
MutPred		0.81		Gain of loop (P = 0.002);Gain of loop (P = 0.002);Gain of loop (P = 0.002);Gain of loop (P = 0.002);Gain of loop (P = 0.002);Gain of loop (P = 0.002);Gain of loop (P = 0.002);Gain of loop (P = 0.002);Gain of loop (P = 0.002);Gain of loop (P = 0.002);Gain of loop (P = 0.002);Gain of loop (P = 0.002);Gain of loop (P = 0.002);Gain of loop (P = 0.002);Gain of loop (P = 0.002);Gain of loop (P = 0.002);
MVP		0.78
MPC		1.6
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.76
gMVP		0.73

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

LitVar

Other links and lift over

dbSNP: rs118203355; hg19: chr9-135801110;