rs796053467

Positions:

• chr9-132896419-C-A
• chr9-132896419-C-G
• chr9-132896419-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000368.5(TSC1):​c.3311G>T​(p.Cys1104Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. C1104Y) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 5.29

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TSC1. . Gene score misZ 2.3217 (greater than the threshold 3.09). Trascript score misZ 3.6986 (greater than threshold 3.09). GenCC has associacion of gene with lung lymphangioleiomyomatosis, tuberous sclerosis 1, tuberous sclerosis, tuberous sclerosis complex, lymphangioleiomyomatosis.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.3311G>T	p.Cys1104Phe	missense_variant	23/23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.3311G>T	p.Cys1104Phe	missense_variant	23/23	1	NM_000368.5	ENSP00000298552	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 05, 2016	In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TSC1-related disease. ClinVar contains an entry for this variant (Variation ID: 207648). This sequence change replaces cysteine with phenylalanine at codon 1104 of the TSC1 protein (p.Cys1104Phe). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and phenylalanine. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 22, 2014

p.Cys1104Phe (TGT>TTT): c.3311 G>T in exon 23 of the TSC1 gene (NM_000368.4). The C1104F variant has not been published as a mutation, nor has it been reported as a benign Polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is Not a common benign variant in these populations. The C1104F variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues Differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved through mammals. In silico analysis predicts this variant is probably damaging to The protein structure/function. However, the vast majority of TSC1 mutations result in protein truncation, while missense mutations have been reported only rarely (Northrup et al., 2011; Au et Al., 2007). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2015

The p.C1104F variant (also known as c.3311G>T), located in coding exon 21 of the TSC1 gene, results from a G to T substitution at nucleotide position 3311. The cysteine at codon 1104 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.06% (greater than 1800 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.C1104F remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	T;.;T;.;.;T;.;T;.;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	.;D;D;D;D;.;.;.;D;D;.
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.72	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.4	M;.;M;.;.;M;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.4	N;N;N;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.61
Sift	Benign	0.044	D;T;D;.;.;.;.;.;.;.;.
Sift4G	Benign	0.13	T;T;T;.;.;.;.;.;.;.;.
Polyphen		1.0	D;.;D;.;.;D;.;D;.;.;.
Vest4		0.67
MutPred		0.37		Gain of methylation at K1099 (P = 0.1714);.;Gain of methylation at K1099 (P = 0.1714);.;.;Gain of methylation at K1099 (P = 0.1714);.;Gain of methylation at K1099 (P = 0.1714);.;.;.;
MVP		0.74
MPC		1.8
ClinPred		0.95	D
GERP RS		5.6
Varity_R		0.43
gMVP		0.41

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: rs796053467; hg19: chr9-135771806;