rs118203720

Variant names:

• chr9-132897590-G-A
• rs118203720
• NM_000368.5:c.2646C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-132897590-G-A
• chr9-132897590-G-T
• chr9-132897590-G-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000368.5(TSC1):​c.2646C>T​(p.Ala882Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00452 in 1,541,130 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A882A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0047 (27 hom.)
• Consequence: TSC1 NM_000368.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23 O:2
• Conservation: PhyloP100: 0.848
• Publications: 5 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 9-132897590-G-A is Benign according to our data. Variant chr9-132897590-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.848 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00271 (384/141600) while in subpopulation NFE AF = 0.00479 (318/66326). AF 95% confidence interval is 0.00436. There are 0 homozygotes in GnomAd4. There are 167 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 384 AD gene.

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.2646C>T	p.Ala882Ala	synonymous	Exon 21 of 23	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.2646C>T	p.Ala882Ala	synonymous	Exon 21 of 23	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.2646C>T	p.Ala882Ala	synonymous	Exon 21 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.2646C>T	p.Ala882Ala	synonymous	Exon 21 of 23	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.2646C>T	p.Ala882Ala	synonymous	Exon 22 of 24	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000643875.1		c.2646C>T	p.Ala882Ala	synonymous	Exon 21 of 23	ENSP00000495158.1	Q92574-1

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 384 AN: 141538 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000902

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00164

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0110

Gnomad NFE AF: 0.00479

Gnomad OTH AF: 0.00363

GnomAD2 exomes AF: 0.00255 AC: 576 AN: 225636 AF XY: 0.00264

Gnomad AFR exome AF: 0.000962

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.000113

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000503

Gnomad NFE exome AF: 0.00441

Gnomad OTH exome AF: 0.00280

GnomAD4 exome AF: 0.00470 AC: 6579 AN: 1399530 Hom.: 27 Cov.: 42 AF XY: 0.00464 AC XY: 3233 AN XY: 696230

African (AFR) AF: 0.000637 AC: 20 AN: 31376

American (AMR) AF: 0.00167 AC: 65 AN: 38818

Ashkenazi Jewish (ASJ) AF: 0.000126 AC: 3 AN: 23888

East Asian (EAS) AF: 0.0000269 AC: 1 AN: 37234

South Asian (SAS) AF: 0.00159 AC: 127 AN: 79960

European-Finnish (FIN) AF: 0.000584 AC: 29 AN: 49648

Middle Eastern (MID) AF: 0.000912 AC: 5 AN: 5482

European-Non Finnish (NFE) AF: 0.00561 AC: 6037 AN: 1076062

Other (OTH) AF: 0.00512 AC: 292 AN: 57062

GnomAD4 genome AF: 0.00271 AC: 384 AN: 141600 Hom.: 0 Cov.: 30 AF XY: 0.00247 AC XY: 167 AN XY: 67660

African (AFR) AF: 0.000900 AC: 35 AN: 38876

American (AMR) AF: 0.00105 AC: 14 AN: 13298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3418

East Asian (EAS) AF: 0.00 AC: 0 AN: 4724

South Asian (SAS) AF: 0.00166 AC: 7 AN: 4228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7640

Middle Eastern (MID) AF: 0.0117 AC: 3 AN: 256

European-Non Finnish (NFE) AF: 0.00479 AC: 318 AN: 66326

Other (OTH) AF: 0.00360 AC: 7 AN: 1944

Alfa AF: 0.00296 Hom.: 2

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	6	not specified (6)
-	-	4	Tuberous sclerosis 1 (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Tuberous sclerosis syndrome (3)
-	-	1	Isolated focal cortical dysplasia type II (1)
-	-	1	Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1854465:Tuberous sclerosis 1 (1)
-	-	-	Malignant tumor of urinary bladder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	9.3
DANN	Benign	0.61
PhyloP100		0.85
Mutation Taster		=98/2	polymorphism

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: rs118203720; hg19: chr9-135772977; COSMIC: COSV104595698; COSMIC: COSV104595698;