9-132905604-G-C

Position:

• chr9-132905604-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4 BP6 BS2

The NM_000368.5(TSC1):​c.1974C>G​(p.Asp658Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D658D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3 O:1
• Conservation: PhyloP100: 0.195

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 -5 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=0.37403247).
• BP6: Variant 9-132905604-G-C is Benign according to our data. Variant chr9-132905604-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48861.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, not_provided=1, Uncertain_significance=3}. Variant chr9-132905604-G-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.1974C>G	p.Asp658Glu	missense_variant	15/23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.1974C>G	p.Asp658Glu	missense_variant	15/23	1	NM_000368.5	ENSP00000298552	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251236 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135800

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461832 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727218

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: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 19, 2024	The p.D658E variant (also known as c.1974C>G), located in coding exon 13 of the TSC1 gene, results from a C to G substitution at nucleotide position 1974. The aspartic acid at codon 658 is replaced by glutamic acid, an amino acid with highly similar properties. In one functional study, this alteration was classified as probably neutral (Hoogeveen-Westerveld M et al. Hum Mutat, 2011 Apr;32:424-35). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	May 08, 2021	- -

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 20, 2023	This missense variant replaces aspartic acid with glutamic acid at codon 658 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 retained more than 80% of wild type TSC1 activity (PMID: 19747374, 21309039). To our knowledge, this variant has not been reported in individuals affected with TSC1-related disorders in the literature. This variant has been identified in 2/251236 chromosomes 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

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 17, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 05, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	9.7
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;.;T;.;.;T;.;T;.;.;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.72	.;T;T;T;T;.;.;.;T;T;.
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.37	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.099	D
MutationAssessor	Uncertain	2.4	M;.;M;.;.;M;.;M;.;.;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.97	N;N;N;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.49
Sift	Benign	0.17	T;T;T;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.011	D;D;D;.;.;.;.;.;.;.;.
Polyphen		0.99	D;.;D;.;.;D;.;D;.;.;.
Vest4		0.34
MutPred		0.48		Loss of loop (P = 0.2237);.;Loss of loop (P = 0.2237);.;.;Loss of loop (P = 0.2237);.;Loss of loop (P = 0.2237);.;Loss of loop (P = 0.2237);.;
MVP		0.71
MPC		0.52
ClinPred		0.66	D
GERP RS		-4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.056
gMVP		0.36

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: rs118203608; hg19: chr9-135780991;