rs397514806

chr9-132896294-C-Achr9-132896294-C-Gchr9-132896294-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4 BP6

The NM_000368.5(TSC1):c.3436G>T(p.Asp1146Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,892 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. D1146E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4 O:1
• Conservation: PhyloP100: 3.50

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 Likely_benign. Variant got -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TSC1
• BP4: Computational evidence support a benign effect (MetaRNN=0.36735982).
• BP6: Variant 9-132896294-C-A is Benign according to our data. Variant chr9-132896294-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 64745.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=2, not_provided=1, Likely_benign=1}. Variant chr9-132896294-C-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.3436G>T	p.Asp1146Tyr	missense_variant	23/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.3436G>T	p.Asp1146Tyr	missense_variant	23/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis syndrome Uncertain:1 Other:1

not provided, no classification provided	curation	Tuberous sclerosis database (TSC1)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 02, 2023	This missense variant replaces aspartic acid with tyrosine at codon 1146 of the TSC1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant has no significant effect on TSC1 protein stability, the TSC1/TSC2 complex, and mTORC1 activity (PMID: 22161988). To our knowledge, this variant has not been reported in individuals affected with TSC1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Tuberous sclerosis 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 16, 2023

Variant summary: TSC1 c.3436G>T (p.Asp1146Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251412 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3436G>T in individuals affected with Tuberous Sclerosis Complex has been reported. At least one publication reports experimental evidence evaluating an impact on protein function and demonstrated there was no significant differences in the T389/S6K ratios, compared to wild-type TSC1 (Hoogeveen_2012). These results showed no damaging effect of this variant. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. The following publication has been ascertained in the context of this evaluation (PMID: 22161988). All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 25, 2020

This variant is associated with the following publications: (PMID: 22161988) -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.35	T;.;T;.;.;T;.;T;.;.;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.37	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.020	D
MutationAssessor	Uncertain	2.5	M;.;M;.;.;M;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.91	N;N;N;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.0040	D;D;D;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.033	D;D;D;.;.;.;.;.;.;.;.
Polyphen		0.94	P;.;P;.;.;P;.;P;.;.;.
Vest4		0.42
MVP		0.53
MPC		1.3
ClinPred		0.84	D
GERP RS		5.7
Varity_R		0.15
gMVP		0.22

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: rs397514806; hg19: chr9-135771681;