rs4962081

Variant names:

• chr9-132897330-G-A
• rs4962081
• NM_000368.5:c.2829C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000368.5(TSC1):​c.2829C>T​(p.Ala943Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.081 in 1,614,032 control chromosomes in the GnomAD database, including 5,782 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.081 (569 hom., cov: 32)
  • Exomes 𝑓: 0.081 (5213 hom.)
• Consequence: TSC1 NM_000368.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22 O:3
• Conservation: PhyloP100: -2.78
• Publications: 31 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 9-132897330-G-A is Benign according to our data. Variant chr9-132897330-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 49006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.78 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.112 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.2829C>T	p.Ala943Ala	synonymous	Exon 22 of 23	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.2829C>T	p.Ala943Ala	synonymous	Exon 22 of 23	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.2829C>T	p.Ala943Ala	synonymous	Exon 22 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.2829C>T	p.Ala943Ala	synonymous	Exon 22 of 23	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.2829C>T	p.Ala943Ala	synonymous	Exon 23 of 24	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000643875.1		c.2829C>T	p.Ala943Ala	synonymous	Exon 22 of 23	ENSP00000495158.1	Q92574-1

Frequencies

GnomAD3 genomes AF: 0.0813 AC: 12355 AN: 152028 Hom.: 567 Cov.: 32

Gnomad AFR AF: 0.0905

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.0536

Gnomad EAS AF: 0.0260

Gnomad SAS AF: 0.0458

Gnomad FIN AF: 0.0438

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0823

Gnomad OTH AF: 0.0815

GnomAD2 exomes AF: 0.0795 AC: 19983 AN: 251450 AF XY: 0.0767

Gnomad AFR exome AF: 0.0887

Gnomad AMR exome AF: 0.153

Gnomad ASJ exome AF: 0.0533

Gnomad EAS exome AF: 0.0282

Gnomad FIN exome AF: 0.0457

Gnomad NFE exome AF: 0.0808

Gnomad OTH exome AF: 0.0768

GnomAD4 exome AF: 0.0810 AC: 118403 AN: 1461886 Hom.: 5213 Cov.: 37 AF XY: 0.0798 AC XY: 58061 AN XY: 727244

African (AFR) AF: 0.0905 AC: 3031 AN: 33480

American (AMR) AF: 0.147 AC: 6585 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0515 AC: 1345 AN: 26136

East Asian (EAS) AF: 0.0295 AC: 1172 AN: 39700

South Asian (SAS) AF: 0.0505 AC: 4355 AN: 86258

European-Finnish (FIN) AF: 0.0466 AC: 2490 AN: 53416

Middle Eastern (MID) AF: 0.0622 AC: 359 AN: 5768

European-Non Finnish (NFE) AF: 0.0848 AC: 94339 AN: 1112008

Other (OTH) AF: 0.0783 AC: 4727 AN: 60396

GnomAD4 genome AF: 0.0813 AC: 12374 AN: 152146 Hom.: 569 Cov.: 32 AF XY: 0.0794 AC XY: 5903 AN XY: 74362

African (AFR) AF: 0.0905 AC: 3754 AN: 41496

American (AMR) AF: 0.116 AC: 1781 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0536 AC: 186 AN: 3468

East Asian (EAS) AF: 0.0260 AC: 135 AN: 5186

South Asian (SAS) AF: 0.0464 AC: 224 AN: 4826

European-Finnish (FIN) AF: 0.0438 AC: 462 AN: 10556

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0823 AC: 5597 AN: 68008

Other (OTH) AF: 0.0806 AC: 170 AN: 2108

Alfa AF: 0.0842 Hom.: 1485

Bravo AF: 0.0894

Asia WGS AF: 0.0390 AC: 136 AN: 3478

EpiCase AF: 0.0826

EpiControl AF: 0.0797

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	7	Tuberous sclerosis 1 (7)
-	-	3	not provided (3)
-	-	2	Tuberous sclerosis syndrome (3)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Isolated focal cortical dysplasia type II (1)
-	-	-	Malignant tumor of urinary bladder (1)
-	-	-	Tuberous sclerosis syndrome;C0751674:Lymphangiomyomatosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.36
DANN	Benign	0.38
PhyloP100		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=89/11	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs4962081; hg19: chr9-135772717; COSMIC: COSV53763996; COSMIC: COSV53763996;