rs1554813610

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_000368.5(TSC1):c.2637G>T(p.Met879Ile) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M879V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000017 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000044 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TSC1
NM_000368.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 4.67

Publications

0 publications found

Variant links:

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

TSC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3432119).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5 link	c.2637G>T	p.Met879Ile	missense_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 link	c.2637G>T	p.Met879Ile	missense_variant	Exon 21 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4 link	c.2637G>T	p.Met879Ile	missense_variant	Exon 22 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes

AF:

0.0000173

AC:

AN:

115774

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000309

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:

0.000263

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000439

AC:

AN:

910438

Hom.:

Cov.:

AF XY:

0.0000343

AC XY:

AN XY:

465804

show subpopulations

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

African (AFR)

AF:

0.0000859

AC:

AN:

23296

American (AMR)

AF:

0.00

AC:

AN:

32938

Ashkenazi Jewish (ASJ)

AF:

0.0000558

AC:

AN:

17920

East Asian (EAS)

AF:

0.000140

AC:

AN:

28548

South Asian (SAS)

AF:

0.00

AC:

AN:

66734

European-Finnish (FIN)

AF:

0.0000253

AC:

AN:

39502

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4032

European-Non Finnish (NFE)

AF:

0.0000470

AC:

AN:

659342

Other (OTH)

AF:

0.0000262

AC:

AN:

38126

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.236

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000173

AC:

AN:

115838

Hom.:

Cov.:

AF XY:

0.0000188

AC XY:

AN XY:

53232

show subpopulations

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

African (AFR)

AF:

0.0000308

AC:

AN:

32428

American (AMR)

AF:

0.00

AC:

AN:

9074

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3090

East Asian (EAS)

AF:

0.00

AC:

AN:

3368

South Asian (SAS)

AF:

0.00

AC:

AN:

2898

European-Finnish (FIN)

AF:

0.000263

AC:

AN:

3808

Middle Eastern (MID)

AF:

0.00

AC:

AN:

158

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

58664

Other (OTH)

AF:

0.00

AC:

AN:

1538

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.250

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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 methionine with isoleucine at codon 879 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). 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 not been identified 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. -

not provided

Uncertain:1

Jun 03, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2 -

Tuberous sclerosis 1

Uncertain:1

Nov 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 879 of the TSC1 protein (p.Met879Ile). This variant is not present in population databases (gnomAD 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: 534471). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC1 protein function with a negative predictive value of 95%. 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

Mar 05, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.M879I variant (also known as c.2637G>T), located in coding exon 19 of the TSC1 gene, results from a G to T substitution at nucleotide position 2637. The methionine at codon 879 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is conserved. 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

Uncertain

0.41

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.49

T;.;T;.;.;T;.;T;.;.;.

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.81

.;T;T;T;T;.;.;.;T;T;.

M_CAP

Benign

0.070

MetaRNN

Benign

0.34

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

1.9

L;.;L;.;.;L;.;L;.;.;.

PhyloP100

4.7

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.9

N;N;N;.;.;.;.;.;.;.;.

REVEL

Uncertain

0.39

Sift

Uncertain

0.013

D;D;D;.;.;.;.;.;.;.;.

Sift4G

Uncertain

0.037

D;D;D;.;.;.;.;.;.;.;.

Polyphen

0.10

B;.;B;.;.;B;.;B;.;.;.

Vest4

0.70

MutPred

0.22

Loss of disorder (P = 0.0521);.;Loss of disorder (P = 0.0521);.;.;Loss of disorder (P = 0.0521);.;Loss of disorder (P = 0.0521);.;.;.;

MVP

0.48

MPC

0.56

ClinPred

0.87

GERP RS

4.9

Varity_R

0.68

gMVP

0.23

Mutation Taster

=67/33

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over