chr9-132925700-C-T

Variant names:

• chr9-132925700-C-T
• rs118203357
• NM_000368.5:c.250G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000368.5(TSC1):​c.250G>A​(p.Ala84Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000342 in 1,614,178 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A84S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (4 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16 O:2
• Conservation: PhyloP100: 0.225
• Publications: 32 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 26 uncertain in NM_000368.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.006469995).
• BP6: Variant 9-132925700-C-T is Benign according to our data. Variant chr9-132925700-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000374 (57/152292) while in subpopulation EAS AF = 0.00579 (30/5182). AF 95% confidence interval is 0.00417. There are 0 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 57 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.250G>A	p.Ala84Thr	missense	Exon 5 of 23	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.250G>A	p.Ala84Thr	missense	Exon 5 of 23	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.250G>A	p.Ala84Thr	missense	Exon 5 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.250G>A	p.Ala84Thr	missense	Exon 5 of 23	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.250G>A	p.Ala84Thr	missense	Exon 6 of 24	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000403810.6	TSL:1	c.250G>A	p.Ala84Thr	missense	Exon 5 of 10	ENSP00000386093.1	Q86WV8

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00558

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000717 AC: 180 AN: 250968 AF XY: 0.000730

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00626

Gnomad EAS exome AF: 0.00408

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000339 AC: 495 AN: 1461886 Hom.: 4 Cov.: 31 AF XY: 0.000340 AC XY: 247 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00612 AC: 160 AN: 26136

East Asian (EAS) AF: 0.00373 AC: 148 AN: 39700

South Asian (SAS) AF: 0.000730 AC: 63 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000656 AC: 73 AN: 1112006

Other (OTH) AF: 0.000629 AC: 38 AN: 60396

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152292 Hom.: 0 Cov.: 33 AF XY: 0.000524 AC XY: 39 AN XY: 74450

African (AFR) AF: 0.00 AC: 0 AN: 41580

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

East Asian (EAS) AF: 0.00579 AC: 30 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000697 Hom.: 2

Bravo AF: 0.000480

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000725 AC: 88

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (6)
-	-	5	Tuberous sclerosis 1 (5)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)
-	-	1	Isolated focal cortical dysplasia type II (1)
-	-	1	Tuberous sclerosis syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Benign	0.91
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.23
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.20
Sift	Benign	0.34	T
Sift4G	Benign	0.086	T
Polyphen		0.0020	B
Vest4		0.26
MVP		0.45
MPC		0.49
ClinPred		0.012	T
GERP RS		-0.86
Varity_R		0.021
gMVP		0.059
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs118203357; hg19: chr9-135801087; COSMIC: COSV53775575;