9-132897550-G-T

Variant names:

• chr9-132897550-G-T
• rs377132822
• NM_000368.5:c.2686C>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000368.5(TSC1):​c.2686C>A​(p.Leu896Ile) 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. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L896F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.63
• Publications: 1 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_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20002049).
• BP6: Variant 9-132897550-G-T is Benign according to our data. Variant chr9-132897550-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 575837.

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.2686C>A	p.Leu896Ile	missense	Exon 21 of 23	NP_000359.1
	TSC1	NM_001406592.1		c.2686C>A	p.Leu896Ile	missense	Exon 21 of 23	NP_001393521.1
	TSC1	NM_001406593.1		c.2686C>A	p.Leu896Ile	missense	Exon 21 of 23	NP_001393522.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	ENST00000298552.9	TSL:1 MANE Select	c.2686C>A	p.Leu896Ile	missense	Exon 21 of 23	ENSP00000298552.3
	TSC1	ENST00000490179.4	TSL:3	c.2686C>A	p.Leu896Ile	missense	Exon 22 of 24	ENSP00000495533.2
	TSC1	ENST00000643875.1		c.2686C>A	p.Leu896Ile	missense	Exon 21 of 23	ENSP00000495158.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248644 AF XY: 0.00

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Feb 20, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L896I variant (also known as c.2686C>A), located in coding exon 19 of the TSC1 gene, results from a C to A substitution at nucleotide position 2686. The leucine at codon 896 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Sep 13, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

Tuberous sclerosis 1 Benign:1

Aug 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.41	T
Eigen	Benign	0.084
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	0.0084	D
MutationAssessor	Benign	1.7	L
PhyloP100		3.6
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.28
Sift	Benign	0.32	T
Sift4G	Uncertain	0.058	T
Polyphen		0.0040	B
Vest4		0.36
MVP		0.49
MPC		0.54
ClinPred		0.24	T
GERP RS		4.7
Varity_R		0.19
gMVP		0.034
Mutation Taster		=87/13	polymorphism

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: rs377132822; hg19: chr9-135772937;