9-132896623-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2 BP4_Moderate BP6

The NM_000368.5(TSC1):c.3107G>A(p.Gly1036Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. G1036K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 1.39

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 -2 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TSC1
• BP4: Computational evidence support a benign effect (MetaRNN=0.24196255).
• BP6: Variant 9-132896623-C-T is Benign according to our data. Variant chr9-132896623-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 486561.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.3107G>A	p.Gly1036Glu	missense_variant	23/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.3107G>A	p.Gly1036Glu	missense_variant	23/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249664 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135288

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461532 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727040

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000810

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

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, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	TSC1: BP4 -

Tuberous sclerosis 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 19, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

TSC1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 10, 2024

The TSC1 c.3107G>A variant is predicted to result in the amino acid substitution p.Gly1036Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2023

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	0.23
BayesDel_addAF	Benign	0.010	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.34	T;.;T;.;.;T;.;T;.;.;.
Eigen	Benign	0.0039
Eigen_PC	Benign	0.0057
FATHMM_MKL	Benign	0.70	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.2	M;.;M;.;.;M;.;M;.;.;.
MutationTaster	Benign	0.88	N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.43	N;N;N;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.0070	D;D;D;.;.;.;.;.;.;.;.
Sift4G	Benign	0.22	T;T;T;.;.;.;.;.;.;.;.
Polyphen		0.93	P;.;P;.;.;P;.;P;.;.;.
Vest4		0.30
MutPred		0.25		Loss of MoRF binding (P = 0.0548);.;Loss of MoRF binding (P = 0.0548);.;.;Loss of MoRF binding (P = 0.0548);.;Loss of MoRF binding (P = 0.0548);.;.;.;
MVP		0.59
MPC		1.1
ClinPred		0.58	D
GERP RS		4.3
Varity_R		0.071
gMVP		0.17

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: rs774196458; hg19: chr9-135772010;