9-132897599-C-A

Position:

• chr9-132897599-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2 BP4

The NM_000368.5(TSC1):​c.2637G>T​(p.Met879Ile) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M879T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000017 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000044 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.67

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 Uncertain_significance. Variant got 0 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=0.3432119).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2637G>T	p.Met879Ile	missense_variant	21/23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.2637G>T	p.Met879Ile	missense_variant	21/23	1	NM_000368.5	ENSP00000298552	P4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2 AN: 115774 Hom.: 0 Cov.: 29 FAILED QC

Gnomad AFR AF: 0.0000309

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: 0.000263

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000439 AC: 40 AN: 910438 Hom.: 0 Cov.: 34 AF XY: 0.0000343 AC XY: 16 AN XY: 465804

Gnomad4 AFR exome AF: 0.0000859

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000558

Gnomad4 EAS exome AF: 0.000140

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000253

Gnomad4 NFE exome AF: 0.0000470

Gnomad4 OTH exome AF: 0.0000262

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000173 AC: 2 AN: 115838 Hom.: 0 Cov.: 29 AF XY: 0.0000188 AC XY: 1 AN XY: 53232

Gnomad4 AFR AF: 0.0000308

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000263

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Aug 15, 2023

This missense variant replaces methionine with isoleucine at codon 879 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 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jun 03, 2022

PM2 -

Tuberous sclerosis 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 18, 2023

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 879 of the TSC1 protein (p.Met879Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 534471). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 05, 2024

The p.M879I variant (also known as c.2637G>T), located in coding exon 19 of the TSC1 gene, results from a G to T substitution at nucleotide position 2637. The methionine at codon 879 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;.;T;.;.;T;.;T;.;.;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	.;T;T;T;T;.;.;.;T;T;.
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.9	L;.;L;.;.;L;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.9	N;N;N;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.013	D;D;D;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.037	D;D;D;.;.;.;.;.;.;.;.
Polyphen		0.10	B;.;B;.;.;B;.;B;.;.;.
Vest4		0.70
MutPred		0.22		Loss of disorder (P = 0.0521);.;Loss of disorder (P = 0.0521);.;.;Loss of disorder (P = 0.0521);.;Loss of disorder (P = 0.0521);.;.;.;
MVP		0.48
MPC		0.56
ClinPred		0.87	D
GERP RS		4.9
Varity_R		0.68
gMVP		0.23

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: rs1554813610; hg19: chr9-135772986;