NM_000368.5:c.*1488C>T

Variant names:

• chr9-132894747-G-A
• rs739442
• NM_000368.5:c.*1488C>T

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.*1488C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 217,942 control chromosomes in the GnomAD database, including 28,141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (18187 hom., cov: 29)
  • Exomes 𝑓: 0.52 (9954 hom.)
• Consequence: TSC1 NM_000368.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.581
• Publications: 16 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=-0.84).
• BP6: Variant 9-132894747-G-A is Benign according to our data. Variant chr9-132894747-G-A is described in ClinVar as Benign. ClinVar VariationId is 365477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.622 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.*1488C>T		3_prime_UTR	Exon 23 of 23	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.*1488C>T		3_prime_UTR	Exon 23 of 23	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.*1488C>T		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.*1488C>T		3_prime_UTR	Exon 23 of 23	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.*1488C>T		3_prime_UTR	Exon 24 of 24	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000643875.1		c.*1488C>T		3_prime_UTR	Exon 23 of 23	ENSP00000495158.1	Q92574-1

Frequencies

GnomAD3 genomes AF: 0.448 AC: 67595 AN: 150714 Hom.: 18192 Cov.: 29

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.546

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.607

Gnomad EAS AF: 0.576

Gnomad SAS AF: 0.640

Gnomad FIN AF: 0.615

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.573

Gnomad OTH AF: 0.464

GnomAD4 exome AF: 0.524 AC: 35222 AN: 67156 Hom.: 9954 Cov.: 0 AF XY: 0.531 AC XY: 16497 AN XY: 31080

African (AFR) AF: 0.114 AC: 384 AN: 3368

American (AMR) AF: 0.433 AC: 879 AN: 2028

Ashkenazi Jewish (ASJ) AF: 0.606 AC: 2570 AN: 4238

East Asian (EAS) AF: 0.535 AC: 5313 AN: 9926

South Asian (SAS) AF: 0.584 AC: 320 AN: 548

European-Finnish (FIN) AF: 0.521 AC: 25 AN: 48

Middle Eastern (MID) AF: 0.459 AC: 192 AN: 418

European-Non Finnish (NFE) AF: 0.555 AC: 22776 AN: 41040

Other (OTH) AF: 0.499 AC: 2763 AN: 5542

GnomAD4 genome AF: 0.448 AC: 67590 AN: 150786 Hom.: 18187 Cov.: 29 AF XY: 0.455 AC XY: 33455 AN XY: 73518

African (AFR) AF: 0.128 AC: 5256 AN: 40908

American (AMR) AF: 0.490 AC: 7432 AN: 15158

Ashkenazi Jewish (ASJ) AF: 0.607 AC: 2105 AN: 3466

East Asian (EAS) AF: 0.575 AC: 2952 AN: 5130

South Asian (SAS) AF: 0.641 AC: 3081 AN: 4804

European-Finnish (FIN) AF: 0.615 AC: 6300 AN: 10240

Middle Eastern (MID) AF: 0.458 AC: 132 AN: 288

European-Non Finnish (NFE) AF: 0.573 AC: 38863 AN: 67794

Other (OTH) AF: 0.466 AC: 973 AN: 2090

Alfa AF: 0.519 Hom.: 26200

Bravo AF: 0.418

Asia WGS AF: 0.581 AC: 2015 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	-0.84
CADD	Benign	0.30
DANN	Benign	0.67
PhyloP100		-0.58
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: rs739442; hg19: chr9-135770134; COSMIC: COSV53765006; COSMIC: COSV53765006;