9-132927276-C-A

Variant names:

• chr9-132927276-C-A
• rs149278759
• NM_000368.5:c.135G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_000368.5(TSC1):​c.135G>T​(p.Leu45Phe) variant causes a missense change. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L45S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.85
• Publications: 0 publications found

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]

TSC1 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• lung lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 23 uncertain in NM_000368.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-132927277-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 534442.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000368.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	NM_000368.5	MANE Select	c.135G>T	p.Leu45Phe	missense	Exon 4 of 23	NP_000359.1
	TSC1	NM_001406615.1		c.-354G>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 24	NP_001393544.1
	TSC1	NM_001406616.1		c.-321G>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 24	NP_001393545.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	ENST00000298552.9	TSL:1 MANE Select	c.135G>T	p.Leu45Phe	missense	Exon 4 of 23	ENSP00000298552.3
	TSC1	ENST00000490179.4	TSL:3	c.135G>T	p.Leu45Phe	missense	Exon 5 of 24	ENSP00000495533.2
	TSC1	ENST00000403810.6	TSL:1	c.135G>T	p.Leu45Phe	missense	Exon 4 of 10	ENSP00000386093.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis syndrome Uncertain:1

Nov 02, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with phenylalanine at codon 45 of the TSC1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TSC1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.9
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.81		Loss of helix (P = 0.028)
MVP		0.92
MPC		1.5
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.59
gMVP		0.64
Mutation Taster		=22/78	disease causing

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

Other links and lift over

dbSNP: rs149278759; hg19: chr9-135802663;