9-132896311-G-A

Variant names:

• chr9-132896311-G-A
• rs751126355
• NM_000368.5:c.3419C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_000368.5(TSC1):​c.3419C>T​(p.Pro1140Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000144 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1140S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:5
• Conservation: PhyloP100: 4.51
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08447793).
• BP6: Variant 9-132896311-G-A is Benign according to our data. Variant chr9-132896311-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 411228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 21 AD gene.

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.3419C>T	p.Pro1140Leu	missense	Exon 23 of 23	NP_000359.1
	TSC1	NM_001406592.1		c.3419C>T	p.Pro1140Leu	missense	Exon 23 of 23	NP_001393521.1
	TSC1	NM_001406593.1		c.3419C>T	p.Pro1140Leu	missense	Exon 23 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.3419C>T	p.Pro1140Leu	missense	Exon 23 of 23	ENSP00000298552.3
	TSC1	ENST00000490179.4	TSL:3	c.3419C>T	p.Pro1140Leu	missense	Exon 24 of 24	ENSP00000495533.2
	TSC1	ENST00000643875.1		c.3419C>T	p.Pro1140Leu	missense	Exon 23 of 23	ENSP00000495158.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000517 AC: 13 AN: 251364 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727244

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112008

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 1 Benign:2

Nov 07, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TSC1-related disorder Uncertain:1

Nov 10, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TSC1 c.3419C>T variant is predicted to result in the amino acid substitution p.Pro1140Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-135771698-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Tuberous sclerosis syndrome Benign:1

Dec 13, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Jun 15, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:1

Jul 28, 2021

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Benign	0.89
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.5	L
PhyloP100		4.5
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.14
Sift	Benign	0.18	T
Sift4G	Uncertain	0.045	D
Polyphen		0.0	B
Vest4		0.11
MutPred		0.14		Loss of glycosylation at P1140 (P = 0.0238)
MVP		0.36
MPC		0.51
ClinPred		0.068	T
GERP RS		3.8
Varity_R		0.031
gMVP		0.099
Mutation Taster		=93/7	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: rs751126355; hg19: chr9-135771698; COSMIC: COSV100051359; COSMIC: COSV100051359;