rs10491534

Variant names:

• chr9-132894301-T-C
• rs10491534
• NM_000368.5:c.*1934A>G

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.*1934A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 231,140 control chromosomes in the GnomAD database, including 2,186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1724 hom., cov: 32)
  • Exomes 𝑓: 0.10 (462 hom.)
• Consequence: TSC1 NM_000368.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.172
• Publications: 17 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=-0.58).
• BP6: Variant 9-132894301-T-C is Benign according to our data. Variant chr9-132894301-T-C is described in ClinVar as Benign. ClinVar VariationId is 365466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.235 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.*1934A>G		3_prime_UTR	Exon 23 of 23	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.*1934A>G		3_prime_UTR	Exon 23 of 23	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.*1934A>G		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.*1934A>G		3_prime_UTR	Exon 23 of 23	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.*1934A>G		3_prime_UTR	Exon 24 of 24	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000643875.1		c.*1934A>G		3_prime_UTR	Exon 23 of 23	ENSP00000495158.1	Q92574-1

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21063 AN: 152076 Hom.: 1724 Cov.: 32

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0814

Gnomad ASJ AF: 0.0957

Gnomad EAS AF: 0.0657

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0922

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.131

GnomAD4 exome AF: 0.100 AC: 7906 AN: 78946 Hom.: 462 Cov.: 0 AF XY: 0.0991 AC XY: 3608 AN XY: 36390

African (AFR) AF: 0.238 AC: 896 AN: 3760

American (AMR) AF: 0.0867 AC: 211 AN: 2434

Ashkenazi Jewish (ASJ) AF: 0.0949 AC: 473 AN: 4984

East Asian (EAS) AF: 0.0346 AC: 383 AN: 11066

South Asian (SAS) AF: 0.130 AC: 89 AN: 686

European-Finnish (FIN) AF: 0.0990 AC: 38 AN: 384

Middle Eastern (MID) AF: 0.0630 AC: 30 AN: 476

European-Non Finnish (NFE) AF: 0.104 AC: 5050 AN: 48580

Other (OTH) AF: 0.112 AC: 736 AN: 6576

GnomAD4 genome AF: 0.139 AC: 21081 AN: 152194 Hom.: 1724 Cov.: 32 AF XY: 0.135 AC XY: 10054 AN XY: 74414

African (AFR) AF: 0.239 AC: 9912 AN: 41498

American (AMR) AF: 0.0813 AC: 1244 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0957 AC: 332 AN: 3468

East Asian (EAS) AF: 0.0655 AC: 340 AN: 5192

South Asian (SAS) AF: 0.102 AC: 493 AN: 4818

European-Finnish (FIN) AF: 0.0922 AC: 977 AN: 10598

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.109 AC: 7431 AN: 68002

Other (OTH) AF: 0.132 AC: 278 AN: 2112

Alfa AF: 0.113 Hom.: 2047

Bravo AF: 0.141

Asia WGS AF: 0.113 AC: 393 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	-0.58
CADD	Benign	3.6
DANN	Benign	0.82
PhyloP100		-0.17
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: rs10491534; hg19: chr9-135769688; COSMIC: COSV108844229; COSMIC: COSV108844229;