9-132891798-C-T

Variant names:

• chr9-132891798-C-T
• rs11553763
• NM_000368.5:c.*4437G>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.*4437G>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 0.104 in 233,568 control chromosomes in the GnomAD database, including 1,765 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1450 hom., cov: 33)
  • Exomes 𝑓: 0.084 (315 hom.)
• Consequence: TSC1 NM_000368.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.820
• Publications: 9 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
• 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=-0.54).
• BP6: Variant 9-132891798-C-T is Benign according to our data. Variant chr9-132891798-C-T is described in ClinVar as Benign. ClinVar VariationId is 365392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	NM_000368.5	MANE Select	c.*4437G>A		3_prime_UTR	Exon 23 of 23	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.*4437G>A		3_prime_UTR	Exon 23 of 23	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.*4437G>A		3_prime_UTR	Exon 23 of 23	NP_001393522.1	Q92574-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	ENST00000298552.9	TSL:1 MANE Select	c.*4437G>A		3_prime_UTR	Exon 23 of 23	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.*4437G>A		3_prime_UTR	Exon 24 of 24	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000646440.2		c.*4437G>A		3_prime_UTR	Exon 23 of 23	ENSP00000495830.2	Q92574-1

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17495 AN: 152100 Hom.: 1443 Cov.: 33

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.0616

Gnomad EAS AF: 0.0550

Gnomad SAS AF: 0.0509

Gnomad FIN AF: 0.0366

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0714

Gnomad OTH AF: 0.118

GnomAD4 exome AF: 0.0836 AC: 6799 AN: 81350 Hom.: 315 Cov.: 0 AF XY: 0.0816 AC XY: 3055 AN XY: 37450

African (AFR) AF: 0.218 AC: 850 AN: 3892

American (AMR) AF: 0.154 AC: 384 AN: 2496

Ashkenazi Jewish (ASJ) AF: 0.0541 AC: 277 AN: 5120

East Asian (EAS) AF: 0.0652 AC: 743 AN: 11398

South Asian (SAS) AF: 0.0456 AC: 32 AN: 702

European-Finnish (FIN) AF: 0.0519 AC: 25 AN: 482

Middle Eastern (MID) AF: 0.0711 AC: 35 AN: 492

European-Non Finnish (NFE) AF: 0.0757 AC: 3784 AN: 50000

Other (OTH) AF: 0.0988 AC: 669 AN: 6768

GnomAD4 genome AF: 0.115 AC: 17538 AN: 152218 Hom.: 1450 Cov.: 33 AF XY: 0.113 AC XY: 8421 AN XY: 74422

African (AFR) AF: 0.215 AC: 8918 AN: 41488

American (AMR) AF: 0.151 AC: 2305 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0616 AC: 214 AN: 3472

East Asian (EAS) AF: 0.0555 AC: 288 AN: 5190

South Asian (SAS) AF: 0.0510 AC: 246 AN: 4826

European-Finnish (FIN) AF: 0.0366 AC: 388 AN: 10612

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0714 AC: 4855 AN: 68030

Other (OTH) AF: 0.116 AC: 246 AN: 2112

Alfa AF: 0.0948 Hom.: 1091

Bravo AF: 0.130

Asia WGS AF: 0.0690 AC: 241 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Isolated focal cortical dysplasia type II (1)
-	-	1	not provided (1)
-	-	1	Tuberous sclerosis 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	14
DANN	Benign	0.81
PhyloP100		0.82
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: rs11553763; hg19: chr9-135767185;