rs1554820281

chr9-132925638-C-Achr9-132925638-C-Gchr9-132925638-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000368.5(TSC1):c.312G>T(p.Lys104Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,202 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.44

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
• 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.312G>T	p.Lys104Asn	missense_variant	5/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.312G>T	p.Lys104Asn	missense_variant	5/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74362

Gnomad4 AFR AF: 0.0000241

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: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 03, 2021

This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with asparagine at codon 104 of the TSC1 protein (p.Lys104Asn). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and asparagine. 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). -

Isolated focal cortical dysplasia type II Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 20, 2023

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2021

The p.K104N variant (also known as c.312G>T), located in coding exon 3 of the TSC1 gene, results from a G to T substitution at nucleotide position 312. The lysine at codon 104 is replaced by asparagine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. 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	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T;.;T;.;T;.;.;.;.;.;.;.;T;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.46	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.3	M;M;.;M;.;M;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.89	D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.82	N;N;.;.;.;.;.;.;.;.;.;.;.;N;.;.
REVEL	Uncertain	0.53
Sift	Uncertain	0.014	D;D;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Sift4G	Uncertain	0.016	D;D;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Polyphen		0.98	D;D;.;D;.;D;.;.;D;D;D;.;.;D;.;.
Vest4		0.73
MutPred		0.47		Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);
MVP		0.88
MPC		1.5
ClinPred		0.86	D
GERP RS		2.5
Varity_R		0.23
gMVP		0.48

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: rs1554820281; hg19: chr9-135801025;