rs1554813594

chr9-132897591-G-A

Variant summary

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

The NM_000368.5(TSC1):c.2645C>T(p.Ala882Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. A882G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.12

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.

• PP2: Missense variant where missense usually causes diseases, TSC1
• BP4: Computational evidence support a benign effect (MetaRNN=0.17948517).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.2645C>T	p.Ala882Val	missense_variant	21/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.2645C>T	p.Ala882Val	missense_variant	21/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1313348 Hom.: 0 Cov.: 40 AF XY: 0.00 AC XY: 0 AN XY: 654122

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 08, 2022

This variant has not been reported in the literature in individuals affected with TSC1-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 466094). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 882 of the TSC1 protein (p.Ala882Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.;T;.;.;T;.;T;.;.;.
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.3	L;.;L;.;.;L;.;L;.;.;.
MutationTaster	Benign	0.91	D;D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.4	N;N;N;.;.;.;.;.;.;.;.
REVEL	Benign	0.23
Sift	Benign	0.24	T;T;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.073	T;T;T;.;.;.;.;.;.;.;.
Polyphen		0.12	B;.;B;.;.;B;.;B;.;.;.
Vest4		0.23
MutPred		0.18		Loss of ubiquitination at K886 (P = 0.0613);.;Loss of ubiquitination at K886 (P = 0.0613);.;.;Loss of ubiquitination at K886 (P = 0.0613);.;Loss of ubiquitination at K886 (P = 0.0613);.;.;.;
MVP		0.38
MPC		0.54
ClinPred		0.73	D
GERP RS		5.8
Varity_R		0.11
gMVP		0.047

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: rs1554813594; hg19: chr9-135772978;