rs199800297

chr9-132907319-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4_Strong BP6

The NM_000368.5(TSC1):c.1315C>G(p.Leu439Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,614,140 control chromosomes in the GnomAD database, with no homozygous occurrence. 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). Synonymous variant affecting the same amino acid position (i.e. L439L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 1.08

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 -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TSC1
• BP4: Computational evidence support a benign effect (MetaRNN=0.021588832).
• BP6: Variant 9-132907319-G-C is Benign according to our data. Variant chr9-132907319-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 466024.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=3, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.1315C>G	p.Leu439Val	missense_variant	13/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.1315C>G	p.Leu439Val	missense_variant	13/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251344 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135850

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461798 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727208

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: 0.0000198

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2 AN XY: 74498

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis 1 Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Oct 24, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jul 11, 2022	The TSC1 c.1315C>G (p.Leu439Val) missense change has a maximum subpopulation frequency of 0.0023% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with tuberous sclerosis complex. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 31, 2023	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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	May 24, 2021	- -

Tuberous sclerosis syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 13, 2023

This missense variant replaces leucine with valine at codon 439 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TSC1-related disorders in the literature. This variant has been identified in 3/282750 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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 20, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	17
Dann	Uncertain	0.98
DEOGEN2	Benign	0.40	T;.;T;.;.;T;.;T;.;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.12	N
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.022	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N;.;N;.;.;N;.;N;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.29	N;N;N;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.12
Sift	Benign	0.87	T;T;T;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.46	T;T;T;.;.;.;.;.;.;.;.;.
Polyphen		0.0010	B;.;B;.;.;B;.;B;.;.;.;.
Vest4		0.097
MVP		0.20
MPC		0.52
ClinPred		0.046	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.039
gMVP		0.13

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: rs199800297; hg19: chr9-135782706;