rs375956049

chr9-132911535-C-Achr9-132911535-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP2

The NM_000368.5(TSC1):c.947G>T(p.Arg316Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R316Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 29)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.32

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-132911536-G-A is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant where missense usually causes diseases, TSC1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.947G>T	p.Arg316Leu	missense_variant	10/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.947G>T	p.Arg316Leu	missense_variant	10/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 29

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

Jan 28, 2022

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. 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. ClinVar contains an entry for this variant (Variation ID: 1002179). This variant has not been reported in the literature in individuals affected with TSC1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 316 of the TSC1 protein (p.Arg316Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.;T;.;T;.;T;.;.;.;.;.;.;.;.;.;.;D;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.4	M;.;M;.;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.98	D;D;D;D;D
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.66	N;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.
REVEL	Uncertain	0.59
Sift	Benign	0.034	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.
Sift4G	Uncertain	0.0090	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.
Polyphen		0.061	B;.;B;.;B;.;B;.;.;.;.;P;P;P;.;.;.;P;.
Vest4		0.66
MutPred		0.62		Loss of phosphorylation at T314 (P = 0.0707);.;Loss of phosphorylation at T314 (P = 0.0707);Loss of phosphorylation at T314 (P = 0.0707);Loss of phosphorylation at T314 (P = 0.0707);Loss of phosphorylation at T314 (P = 0.0707);Loss of phosphorylation at T314 (P = 0.0707);Loss of phosphorylation at T314 (P = 0.0707);Loss of phosphorylation at T314 (P = 0.0707);.;.;Loss of phosphorylation at T314 (P = 0.0707);Loss of phosphorylation at T314 (P = 0.0707);Loss of phosphorylation at T314 (P = 0.0707);Loss of phosphorylation at T314 (P = 0.0707);Loss of phosphorylation at T314 (P = 0.0707);.;Loss of phosphorylation at T314 (P = 0.0707);.;
MVP		0.93
MPC		0.67
ClinPred		0.74	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs375956049; hg19: chr9-135786922;