chr9-132896627-C-T

Position:

• chr9-132896627-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_000368.5(TSC1):​c.3103G>A​(p.Gly1035Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,613,806 control chromosomes in the GnomAD database, including 7 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (6 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:17 O:2
• Conservation: PhyloP100: 0.846

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TSC1. . Gene score misZ 2.3217 (greater than the threshold 3.09). Trascript score misZ 3.6986 (greater than threshold 3.09). GenCC has associacion of gene with lung lymphangioleiomyomatosis, tuberous sclerosis 1, tuberous sclerosis, tuberous sclerosis complex, lymphangioleiomyomatosis.
• BP4: Computational evidence support a benign effect (MetaRNN=0.005901724).
• BP6: Variant 9-132896627-C-T is Benign according to our data. Variant chr9-132896627-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41696.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, not_provided=2, Benign=10}. Variant chr9-132896627-C-T is described in Lovd as [Likely_benign]. Variant chr9-132896627-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00138 (210/152252) while in subpopulation NFE AF= 0.00215 (146/68016). AF 95% confidence interval is 0.00186. There are 1 homozygotes in gnomad4. There are 92 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 210 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.3103G>A	p.Gly1035Ser	missense_variant	23/23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.3103G>A	p.Gly1035Ser	missense_variant	23/23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.3103G>A	p.Gly1035Ser	missense_variant	24/24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes AF: 0.00138 AC: 210 AN: 152132 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00139 AC: 348 AN: 249584 Hom.: 1 AF XY: 0.00126 AC XY: 170 AN XY: 135288

Gnomad AFR exome AF: 0.000255

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.00379

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.00201

Gnomad OTH exome AF: 0.00214

GnomAD4 exome AF: 0.00214 AC: 3126 AN: 1461554 Hom.: 6 Cov.: 31 AF XY: 0.00209 AC XY: 1520 AN XY: 727062

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00150

Gnomad4 ASJ exome AF: 0.00279

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000244

Gnomad4 NFE exome AF: 0.00255

Gnomad4 OTH exome AF: 0.00205

GnomAD4 genome AF: 0.00138 AC: 210 AN: 152252 Hom.: 1 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74462

Gnomad4 AFR AF: 0.000554

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00215

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00209 Hom.: 2

Bravo AF: 0.00156

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00140 AC: 170

EpiCase AF: 0.00289

EpiControl AF: 0.00314

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:17 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:6 Other:1

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 04, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 2013	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	Genetic Services Laboratory, University of Chicago	Aug 19, 2021	- -

not provided Uncertain:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	TSC1: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 31, 2016	Variant Summary: The c.3103G>A (p.Gly1035Ser) in TSC1 gene is a missense change that involves a non-conserved nucleotide and 3/4 in silico programs predicting a "benign" outcome. The variant of interest was observed in controls with an allele frequency of 0.0014 (170/119052chrs tested) which exceeds the predicted maximum expected allele frequency for a pathogenic variant in this gene (0.0025). The variant of interest has been reported in multiple affected individuals in cis with a pathogenic variant (Nellist, 2009, TSC1 db).In the functional studies the G1035S had similar activities as wt (Nellist, 2009). In addition, multiple reputable databases/clinical laboratories and publications cite the variant with a classification of "Neutral/likely benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as a Benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -

Tuberous sclerosis 1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 09, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 25, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 03, 2014	This alteration is classified as 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	Sep 24, 2020	- -

Isolated focal cortical dysplasia type II Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 25, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Tuberous sclerosis syndrome Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC1)

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	13
DANN	Benign	0.93
DEOGEN2	Benign	0.29	T;.;T;.;.;T;.;T;.;.;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.68	.;T;T;T;T;.;.;.;T;T;.
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.0059	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.9	M;.;M;.;.;M;.;M;.;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.70	N;N;N;.;.;.;.;.;.;.;.
REVEL	Benign	0.17
Sift	Benign	0.17	T;T;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.75	T;T;T;.;.;.;.;.;.;.;.
Polyphen		0.044	B;.;B;.;.;B;.;B;.;.;.
Vest4		0.11
MVP		0.75
MPC		0.50
ClinPred		0.0073	T
GERP RS		4.3
Varity_R		0.020
gMVP		0.15

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

Publications

LitVar

Other links and lift over

dbSNP: rs118203742; hg19: chr9-135772014; COSMIC: COSV53772381; COSMIC: COSV53772381;