rs1249697208

Variant names:

• chr9-132897423-C-T
• rs1249697208
• NM_000368.5:c.2813G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000368.5(TSC1):​c.2813G>A​(p.Arg938Lys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 missense, splice_region
• Scores: Splicing: ADA: 0.9994
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2813G>A	p.Arg938Lys	missense_variant, splice_region_variant	Exon 21 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.2813G>A	p.Arg938Lys	missense_variant, splice_region_variant	Exon 21 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.2813G>A	p.Arg938Lys	missense_variant, splice_region_variant	Exon 22 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251462 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135898

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis syndrome Uncertain:1

Aug 15, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with lysine at codon 938 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). However, this variant causes a G>A nucleotide substitution at the last nucleotide of exon 21 of the TSC1 gene, and splice site prediction tools suggest that this variant may impact RNA splicing. 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 1/251462 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. -

Tuberous sclerosis 1 Uncertain:1

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 938 of the TSC1 protein (p.Arg938Lys). This variant also falls at the last nucleotide of exon 21, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 534414). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TSC1 protein function with a negative predictive value of 95%. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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

Jan 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R938K variant (also known as c.2813G>A), located in coding exon 19 of the TSC1 gene, results from a G to A substitution at nucleotide position 2813. The amino acid change results in arginine to lysine at codon 938, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 19, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is well conserved in available vertebrate species. This amino acid position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition, as a missense substitution this is predicted to be tolerated by in silico analysis. 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	Benign	0.10
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.30	T;.;T;.;.;T;.;T;.;.;.
Eigen	Benign	0.056
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.82	.;T;T;T;T;.;.;.;T;T;.
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.1	L;.;L;.;.;L;.;L;.;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.34	N;N;N;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.30
Sift	Benign	0.57	T;T;T;.;.;.;.;.;.;.;.
Sift4G	Benign	1.0	T;T;T;.;.;.;.;.;.;.;.
Polyphen		0.025	B;.;B;.;.;B;.;B;.;.;.
Vest4		0.24
MutPred		0.24		Gain of ubiquitination at R938 (P = 0.0198);.;Gain of ubiquitination at R938 (P = 0.0198);.;.;Gain of ubiquitination at R938 (P = 0.0198);.;Gain of ubiquitination at R938 (P = 0.0198);.;.;.;
MVP		0.66
MPC		0.52
ClinPred		0.32	T
GERP RS		5.4
Varity_R		0.32
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.88		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1249697208; hg19: chr9-135772810;