9-132925678-G-C

Position:

• chr9-132925678-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The ENST00000298552.9(TSC1):​c.272C>G​(p.Ser91Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,196 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S91L) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: TSC1 ENST00000298552.9 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.40

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 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 16 uncertain in ENST00000298552.9
• 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.272C>G	p.Ser91Trp	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.272C>G	p.Ser91Trp	missense_variant	5/23	1	NM_000368.5	ENSP00000298552	P4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74342

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 29, 2021

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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with TSC1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with tryptophan at codon 91 of the TSC1 protein (p.Ser91Trp). The serine residue is moderately conserved and there is a large physicochemical difference between serine and tryptophan. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2022

The p.S91W variant (also known as c.272C>G), located in coding exon 3 of the TSC1 gene, results from a C to G substitution at nucleotide position 272. The serine at codon 91 is replaced by tryptophan, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;D;.;D;.;D;.;.;.;.;.;.;.;D;.;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	.;D;D;.;.;.;D;D;.;.;D;D;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.1	M;M;.;M;.;M;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.5	N;N;.;.;.;.;.;.;.;.;.;.;.;N;.;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D;D;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Sift4G	Pathogenic	0.0010	D;D;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Polyphen		0.98	D;D;.;D;.;D;.;.;D;D;D;.;.;D;.;.
Vest4		0.68
MutPred		0.65		Gain of MoRF binding (P = 0.0334);Gain of MoRF binding (P = 0.0334);Gain of MoRF binding (P = 0.0334);Gain of MoRF binding (P = 0.0334);Gain of MoRF binding (P = 0.0334);Gain of MoRF binding (P = 0.0334);Gain of MoRF binding (P = 0.0334);Gain of MoRF binding (P = 0.0334);Gain of MoRF binding (P = 0.0334);Gain of MoRF binding (P = 0.0334);Gain of MoRF binding (P = 0.0334);Gain of MoRF binding (P = 0.0334);Gain of MoRF binding (P = 0.0334);Gain of MoRF binding (P = 0.0334);Gain of MoRF binding (P = 0.0334);Gain of MoRF binding (P = 0.0334);
MVP		0.82
MPC		1.6
ClinPred		0.83	D
GERP RS		2.5
Varity_R		0.22
gMVP		0.52

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: rs118203361; hg19: chr9-135801065;