NM_000368.5:c.1078A>G

Variant names:

• chr9-132911065-T-C
• rs201738258
• NM_000368.5:c.1078A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_000368.5(TSC1):​c.1078A>G​(p.Thr360Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000142 in 1,614,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. T360P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 3.61
• Publications: 2 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2250092).
• BP6: Variant 9-132911065-T-C is Benign according to our data. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446. Variant chr9-132911065-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534446.
• BS2: High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.1078A>G	p.Thr360Ala	missense_variant	Exon 11 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.1078A>G	p.Thr360Ala	missense_variant	Exon 11 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.1078A>G	p.Thr360Ala	missense_variant	Exon 12 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152148 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251336 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1112008

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152266 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74460

African (AFR) AF: 0.00 AC: 0 AN: 41548

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis 1 Uncertain:1 Benign:2

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 14, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

May 05, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Jan 10, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.26	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.23	T
PhyloP100		3.6
ClinPred		0.59	D
GERP RS		5.7
Varity_R		0.12
Mutation Taster		=85/15	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: rs201738258; hg19: chr9-135786452;