9-132897612-T-G

Variant names:

• chr9-132897612-T-G
• rs118203717
• NM_000368.5:c.2626-2A>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000368.5(TSC1):​c.2626-2A>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000115 in 871,522 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TSC1 NM_000368.5 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.57
• 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3, offset of 7, new splice context is: ttttttttttccggaagtAGaaa. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-132897612-T-G is Pathogenic according to our data. Variant chr9-132897612-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 576564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000368.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	NM_000368.5	MANE Select	c.2626-2A>C		splice_acceptor intron	N/A	NP_000359.1
	TSC1	NM_001406592.1		c.2626-2A>C		splice_acceptor intron	N/A	NP_001393521.1
	TSC1	NM_001406593.1		c.2626-2A>C		splice_acceptor intron	N/A	NP_001393522.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	ENST00000298552.9	TSL:1 MANE Select	c.2626-2A>C		splice_acceptor intron	N/A	ENSP00000298552.3
	TSC1	ENST00000490179.4	TSL:3	c.2626-2A>C		splice_acceptor intron	N/A	ENSP00000495533.2
	TSC1	ENST00000643875.1		c.2626-2A>C		splice_acceptor intron	N/A	ENSP00000495158.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 43678 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

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 AF: 0.00000115 AC: 1 AN: 871522 Hom.: 0 Cov.: 33 AF XY: 0.00000228 AC XY: 1 AN XY: 438864

⚠️ 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: 23544

American (AMR) AF: 0.00 AC: 0 AN: 22736

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15378

East Asian (EAS) AF: 0.00 AC: 0 AN: 29854

South Asian (SAS) AF: 0.00 AC: 0 AN: 41894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28664

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3220

European-Non Finnish (NFE) AF: 0.00000150 AC: 1 AN: 668792

Other (OTH) AF: 0.00 AC: 0 AN: 37440

⚠️ 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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 43678 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 20346

African (AFR) AF: 0.00 AC: 0 AN: 17788

American (AMR) AF: 0.00 AC: 0 AN: 3368

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 714

East Asian (EAS) AF: 0.00 AC: 0 AN: 1188

South Asian (SAS) AF: 0.00 AC: 0 AN: 862

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 80

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 17422

Other (OTH) AF: 0.00 AC: 0 AN: 542

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000167 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis syndrome Pathogenic:1

Dec 05, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2626-2A>C variant in TSC1 has not been reported in individuals with tuberous sclerosis (TSC) and was absent from large population studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Another nucleotide change at this position (c.2626-2A>G) has been reported in an individual with TSC (Au 2007), supporting that variation at position c.2626-2 leads to loss of TSC1 function. Heterozygous loss-of-function of the TSC1 gene is an established disease mechanism in individuals with tuberous sclerosis. In summary, this variant meets our criteria to be classified as pathogenic for tuberous sclerosis in an autosomal dominant manner based upon the predicted impact to the protein. ACMG/AMP Criteria applied: PVS1; PM5; PM2.

Tuberous sclerosis 1 Pathogenic:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 20 of the TSC1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TSC1 are known to be pathogenic (PMID: 10227394, 17304050). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with tuberous sclerosis complex (PMID: 35918040; internal data). ClinVar contains an entry for this variant (Variation ID: 576564). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Hereditary cancer-predisposing syndrome Pathogenic:1

Dec 30, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2626-2A>C intronic variant results from an A to C substitution two nucleotides upstream from coding exon 19 in the TSC1 gene. This alteration has been identified in a tuberous sclerosis complex (TSC) cohort (Ng SY et al. Eur J Med Genet, 2022 Oct;65:104573). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is classified as likely pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	35
DANN	Uncertain	0.98
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		7.6
GERP RS		4.6
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: -9
DS_AL_spliceai		1.0		Position offset: -2

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

Other links and lift over

dbSNP: rs118203717; hg19: chr9-135772999;