chr9-132897610-C-T

Variant names:

• chr9-132897610-C-T
• rs747602915
• NM_000368.5:c.2626G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000368.5(TSC1):​c.2626G>A​(p.Glu876Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000854 in 1,170,912 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E876E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 8.5e-7 (0 hom.)
• Consequence: TSC1 NM_000368.5 missense, splice_region
• Scores: Splicing: ADA: 0.9983
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.49
• Publications: 4 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 3 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2626G>A	p.Glu876Lys	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.2626G>A	p.Glu876Lys	missense_variant, splice_region_variant	Exon 21 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.2626G>A	p.Glu876Lys	missense_variant, splice_region_variant	Exon 22 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 8.54e-7 AC: 1 AN: 1170912 Hom.: 0 Cov.: 42 AF XY: 0.00000171 AC XY: 1 AN XY: 585900

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27928

American (AMR) AF: 0.00 AC: 0 AN: 29696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20118

East Asian (EAS) AF: 0.00 AC: 0 AN: 33416

South Asian (SAS) AF: 0.00 AC: 0 AN: 63692

European-Finnish (FIN) AF: 0.0000272 AC: 1 AN: 36792

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4806

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 906024

Other (OTH) AF: 0.00 AC: 0 AN: 48440

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 26

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1854465:Tuberous sclerosis 1 Uncertain:1

Feb 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tuberous sclerosis 1 Uncertain:1

Aug 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 534429). 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 glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 876 of the TSC1 protein (p.Glu876Lys). -

Hereditary cancer-predisposing syndrome Uncertain:1

Oct 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E876K variant (also known as c.2626G>A), located in coding exon 19 of the TSC1 gene, results from a G to A substitution at nucleotide position 2626. This variant impacts the first base pair of coding exon 19. The glutamic acid at codon 876 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D;.;D;.;.;D;.;D;.;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	.;D;D;D;D;.;.;.;D;D;.
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.63	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.0	M;.;M;.;.;M;.;M;.;.;.
PhyloP100		7.5
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.8	D;D;D;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.58
Sift	Benign	0.083	T;T;T;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.060	T;T;T;.;.;.;.;.;.;.;.
Polyphen		1.0	D;.;D;.;.;D;.;D;.;.;.
Vest4		0.89
MutPred		0.24		Gain of MoRF binding (P = 0.0022);.;Gain of MoRF binding (P = 0.0022);.;.;Gain of MoRF binding (P = 0.0022);.;Gain of MoRF binding (P = 0.0022);.;.;.;
MVP		0.84
MPC		1.5
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.61
gMVP		0.50
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.77
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: rs747602915; hg19: chr9-135772997;