9-132906052-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000368.5(TSC1):c.1526G>A(p.Arg509Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,614,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. R509L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00063 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:2
• Conservation: PhyloP100: 0.660

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TSC1
• BP4: Computational evidence support a benign effect (MetaRNN=0.01075694).
• BP6: Variant 9-132906052-C-T is Benign according to our data. Variant chr9-132906052-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 48797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132906052-C-T is described in Lovd as [Pathogenic]. Variant chr9-132906052-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000631 (96/152222) while in subpopulation AFR AF= 0.00224 (93/41548). AF 95% confidence interval is 0.00187. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 96 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.1526G>A	p.Arg509Gln	missense_variant	15/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.1526G>A	p.Arg509Gln	missense_variant	15/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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

GnomAD3 exomes AF: 0.000156 AC: 39 AN: 250572 Hom.: 0 AF XY: 0.0000812 AC XY: 11 AN XY: 135526

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000595 AC: 87 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.0000509 AC XY: 37 AN XY: 727210

Gnomad4 AFR exome AF: 0.00173

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000631 AC: 96 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.000564 AC XY: 42 AN XY: 74408

Gnomad4 AFR AF: 0.00224

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000114 Hom.: 0

Bravo AF: 0.000589

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000189 AC: 23

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 02, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 08, 2019	Variant summary: TSC1 c.1526G>A (p.Arg509Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 276324 control chromosomes, predominantly at a frequency of 0.002 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 80 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 a benign polymorphism found primarily in populations of African origin. c.1526G>A has been reported in the literature in a child of African origin with multiple congenital malformations and no signs of Tuberous Sclerosis Complex (TSC); the variant was also identified in one of the parents (no signs of TSC). Experimental evidence evaluating an impact on protein function demonstrated the variant to display similar values to the wild type and be active in immunoblotting assay and to not affect TSC1 function (Hoogeveen-Westerveld_2011, Nellist_2009). Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign (2x) and once as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Tuberous sclerosis 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 23, 2023	This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 22, 2018	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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 31, 2020	- -

Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1854465:Tuberous sclerosis 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 12, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2022

TSC1: BS1, BS2 -

Tuberous sclerosis syndrome 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	0.071
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;.;T;.;.;T;.;T;.;.;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.81	D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.011	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.77	N;.;N;.;.;N;.;N;.;.;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.81	N;N;N;.;.;.;.;.;.;.;.
REVEL	Benign	0.20
Sift	Benign	0.072	T;T;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.64	T;T;T;.;.;.;.;.;.;.;.
Polyphen		0.011	B;.;B;.;.;B;.;B;.;.;.
Vest4		0.25
MVP		0.61
MPC		0.59
ClinPred		0.0071	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.048
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs118203543; hg19: chr9-135781439;