rs1060503206

Variant names:

• chr9-132923408-G-A
• rs1060503206
• NM_000368.5:c.448C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-132923408-G-A
• chr9-132923408-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000368.5(TSC1):​c.448C>T​(p.His150Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. H150P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.60
• Publications: 0 publications found

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]

TSC1 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• lung lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 25 uncertain in NM_000368.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.448C>T	p.His150Tyr	missense_variant	Exon 6 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.448C>T	p.His150Tyr	missense_variant	Exon 6 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.448C>T	p.His150Tyr	missense_variant	Exon 7 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461856 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis 1 Uncertain:1

Aug 28, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine with tyrosine at codon 150 of the TSC1 protein (p.His150Tyr). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is not present in population databases (ExAC 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: 411243). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The tyrosine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.41	T;.;T;.;T;.;T;.;.;.;.;.;.;.;.;.;.;T;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	0.038
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	.;D;D;D;.;.;.;D;D;.;D;.;.;D;D;D;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.47	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.2	L;.;L;.;L;.;L;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		5.6
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.93	N;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.
REVEL	Uncertain	0.33
Sift	Benign	0.63	T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.
Sift4G	Benign	0.45	T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.
Polyphen		0.0010	B;.;B;.;B;.;B;.;.;.;.;B;B;B;.;.;.;B;.;.
Vest4		0.29
MutPred		0.76		Gain of helix (P = 0.0425);.;Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);.;.;Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);.;Gain of helix (P = 0.0425);.;Gain of helix (P = 0.0425);
MVP		0.69
MPC		0.59
ClinPred		0.97	D
GERP RS		4.2
Varity_R		0.044
gMVP		0.58
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs1060503206; hg19: chr9-135798795;