rs199620268

chr9-132925604-A-Cchr9-132925604-A-Gchr9-132925604-A-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 3P and 11B. PM5 PP2 BP4_Moderate BP6 BS1 BS2

The NM_000368.5(TSC1):c.346T>G(p.Leu116Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00046 in 1,614,226 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. L116F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00048 (0 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:13 O:3
• Conservation: PhyloP100: 2.04

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 Benign. Variant got -8 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-132925602-TAA-TGG is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant where missense usually causes diseases, TSC1
• BP4: Computational evidence support a benign effect (MetaRNN=0.08484614).
• BP6: Variant 9-132925604-A-C is Benign according to our data. Variant chr9-132925604-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 64814.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, not_provided=3, Benign=6, Uncertain_significance=1}. Variant chr9-132925604-A-C is described in Lovd as [Likely_benign]. Variant chr9-132925604-A-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000477 (698/1461888) while in subpopulation NFE AF= 0.000549 (610/1112006). AF 95% confidence interval is 0.000512. There are 0 homozygotes in gnomad4_exome. There are 321 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 45 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.346T>G	p.Leu116Val	missense_variant	5/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.346T>G	p.Leu116Val	missense_variant	5/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

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: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000382 AC: 96 AN: 251236 Hom.: 0 AF XY: 0.000361 AC XY: 49 AN XY: 135766

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00115

Gnomad NFE exome AF: 0.000572

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000477 AC: 698 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.000441 AC XY: 321 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00110

Gnomad4 NFE exome AF: 0.000549

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000295 AC: 45 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74492

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000391 Hom.: 4

Bravo AF: 0.000212

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000313 AC: 38

EpiCase AF: 0.000436

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:13 Other:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 08, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 15, 2015	- -

Tuberous sclerosis syndrome Uncertain:1 Benign:1 Other:1

Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Aug 01, 2016	Found in patient having exome sequencing for an unrelated indication. No known history of Tuberous sclerosis complex. -
not provided, no classification provided	curation	Tuberous sclerosis database (TSC1)	-	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

Tuberous sclerosis 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 12, 2023	Variant summary: TSC1 c.346T>G (p.Leu116Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 251236 control chromosomes (gnomAD). The observed variant frequency is approximately 15 fold of the estimated maximal expected allele frequency for a pathogenic variant in TSC1 causing Tuberous Sclerosis Complex phenotype (2.5e-05), strongly suggesting that the variant is benign. c.346T>G has been reported in the literature in an individual with, or suspected of having, Tuberous Sclerosis Complex without strong evidence for causality (Hoogeveen-Westerveld_2011). This same report included an in vitro study which showed the variant did not have a significantly higher T389/S6K ratio than wild-type TSC1-TSC2, however TORC1 activity was estimated, not measured, and therefore this report is only indirect evidence for the benign nature of the variant. Eleven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, classifying the variant as either benign (n=4)/likely benign (n=5), or VUS (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 28, 2019	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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 03, 2020	- -

TSC1-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 30, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Isolated focal cortical dysplasia type II Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autism spectrum disorder Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC1)

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Uncertain	0.13
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.50	T;T;.;T;.;T;.;.;.;.;.;.;.;T;.;.
Eigen	Benign	0.037
Eigen_PC	Benign	-0.047
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.085	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.5	M;M;.;M;.;M;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.0	N;N;.;.;.;.;.;.;.;.;.;.;.;N;.;.
REVEL	Uncertain	0.45
Sift	Benign	0.19	T;T;.;.;.;.;.;.;.;.;.;.;.;T;.;.
Sift4G	Uncertain	0.0090	D;D;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Polyphen		0.72	P;P;.;P;.;P;.;.;P;P;P;.;.;P;.;.
Vest4		0.84
MVP		0.72
MPC		1.4
ClinPred		0.085	T
GERP RS		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.10
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199620268; hg19: chr9-135800991;