9-132892556-C-T

Variant names:

• chr9-132892556-C-T
• rs1050700
• NM_000368.5:c.*3679G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000368.5(TSC1):​c.*3679G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.697 in 233,098 control chromosomes in the GnomAD database, including 56,939 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (36245 hom., cov: 32)
  • Exomes 𝑓: 0.71 (20694 hom.)
• Consequence: TSC1 NM_000368.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.68
• Publications: 18 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 9-132892556-C-T is Benign according to our data. Variant chr9-132892556-C-T is described in ClinVar as Benign. ClinVar VariationId is 365414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.799 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.*3679G>A		3_prime_UTR_variant	Exon 23 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.*3679G>A		3_prime_UTR_variant	Exon 23 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.*3679G>A		3_prime_UTR_variant	Exon 24 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes AF: 0.688 AC: 104476 AN: 151944 Hom.: 36217 Cov.: 32

Gnomad AFR AF: 0.612

Gnomad AMI AF: 0.674

Gnomad AMR AF: 0.648

Gnomad ASJ AF: 0.741

Gnomad EAS AF: 0.810

Gnomad SAS AF: 0.819

Gnomad FIN AF: 0.795

Gnomad MID AF: 0.655

Gnomad NFE AF: 0.705

Gnomad OTH AF: 0.671

GnomAD4 exome AF: 0.714 AC: 57832 AN: 81036 Hom.: 20694 Cov.: 0 AF XY: 0.716 AC XY: 26708 AN XY: 37282

African (AFR) AF: 0.619 AC: 2411 AN: 3896

American (AMR) AF: 0.634 AC: 1587 AN: 2502

Ashkenazi Jewish (ASJ) AF: 0.751 AC: 3846 AN: 5124

East Asian (EAS) AF: 0.798 AC: 9107 AN: 11410

South Asian (SAS) AF: 0.815 AC: 572 AN: 702

European-Finnish (FIN) AF: 0.750 AC: 42 AN: 56

Middle Eastern (MID) AF: 0.656 AC: 324 AN: 494

European-Non Finnish (NFE) AF: 0.703 AC: 35233 AN: 50086

Other (OTH) AF: 0.696 AC: 4710 AN: 6766

GnomAD4 genome AF: 0.688 AC: 104556 AN: 152062 Hom.: 36245 Cov.: 32 AF XY: 0.694 AC XY: 51582 AN XY: 74348

African (AFR) AF: 0.612 AC: 25384 AN: 41462

American (AMR) AF: 0.648 AC: 9899 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.741 AC: 2574 AN: 3472

East Asian (EAS) AF: 0.810 AC: 4177 AN: 5158

South Asian (SAS) AF: 0.820 AC: 3954 AN: 4822

European-Finnish (FIN) AF: 0.795 AC: 8416 AN: 10584

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.705 AC: 47920 AN: 67964

Other (OTH) AF: 0.675 AC: 1427 AN: 2114

Alfa AF: 0.693 Hom.: 61548

Bravo AF: 0.669

Asia WGS AF: 0.817 AC: 2840 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Tuberous sclerosis 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Isolated focal cortical dysplasia type II Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.14
DANN	Benign	0.73
PhyloP100		-3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs1050700; hg19: chr9-135767943;