9-132910615-C-G

Variant names:

• chr9-132910615-C-G
• rs769331772
• NM_000368.5:c.1219G>C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000368.5(TSC1):​c.1219G>C​(p.Val407Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. V407M) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.17

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08486578).
• BP6: Variant 9-132910615-C-G is Benign according to our data. Variant chr9-132910615-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 655839.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.1219G>C	p.Val407Leu	missense_variant	Exon 12 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.1219G>C	p.Val407Leu	missense_variant	Exon 12 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.1219G>C	p.Val407Leu	missense_variant	Exon 13 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251112 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135714

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: 6.84e-7 AC: 1 AN: 1461832 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727226

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Oct 31, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TSC1 c.1219G>C (p.Val407Leu) variant has been reported in the published literature in an individual undergoing genetic testing due to suspected tuberous sclerosis (PMID: 32917966 (2021)). The frequency of this variant in the general population, 0.000004 (1/251112 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Uncertain:1

Jan 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V407L variant (also known as c.1219G>C), located in coding exon 10 of the TSC1 gene, results from a G to C substitution at nucleotide position 1219. The valine at codon 407 is replaced by leucine, an amino acid with highly similar properties. This alteration was identified in 1 of 374 patients with clinically suspected TSC undergoing genetic testing within the TSC1 and TSC2 genes, but no specific phenotypic data was provided (Meng Y et al. J Hum Genet, 2021 Mar;66:227-236). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Tuberous sclerosis 1 Benign:1

Oct 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	11
DANN	Benign	0.95
DEOGEN2	Uncertain	0.45	T;.;T;.;T;.;T;.;.;.;.;.;.;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.68	.;T;T;T;.;.;.;T;T;.;.;.;T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.085	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.5	L;.;L;.;L;.;L;.;.;.;.;.;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.41	N;N;N;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.12
Sift	Benign	0.20	T;T;T;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.48	T;T;T;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.0040	B;.;B;.;B;.;B;.;.;.;B;B;B;.
Vest4		0.28
MutPred		0.39		Gain of phosphorylation at S403 (P = 0.1971);.;Gain of phosphorylation at S403 (P = 0.1971);.;Gain of phosphorylation at S403 (P = 0.1971);.;Gain of phosphorylation at S403 (P = 0.1971);.;Gain of phosphorylation at S403 (P = 0.1971);.;Gain of phosphorylation at S403 (P = 0.1971);Gain of phosphorylation at S403 (P = 0.1971);Gain of phosphorylation at S403 (P = 0.1971);.;
MVP		0.55
MPC		0.50
ClinPred		0.075	T
GERP RS		3.5
Varity_R		0.025
gMVP		0.18

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: rs769331772; hg19: chr9-135786002;