rs118203500

Variant names:

• chr9-132910712-CAT-C
• rs118203500
• NM_000368.5:c.1142-22_1142-21delAT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000368.5(TSC1):​c.1142-22_1142-21delAT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00081 in 1,612,954 control chromosomes in the GnomAD database, including 16 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0043 (13 hom., cov: 31)
  • Exomes 𝑓: 0.00044 (3 hom.)
• Consequence: TSC1 NM_000368.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 2.13
• Publications: 0 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: Ambry Genetics, PanelApp Australia, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• 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 -10 ACMG points.

• BP6: Variant 9-132910712-CAT-C is Benign according to our data. Variant chr9-132910712-CAT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 48746.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00435 (662/152256) while in subpopulation AFR AF = 0.0153 (636/41536). AF 95% confidence interval is 0.0143. There are 13 homozygotes in GnomAd4. There are 336 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 662 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	NM_000368.5	MANE Select	c.1142-22_1142-21delAT		intron	N/A	NP_000359.1
	TSC1	NM_001406592.1		c.1142-22_1142-21delAT		intron	N/A	NP_001393521.1
	TSC1	NM_001406593.1		c.1142-22_1142-21delAT		intron	N/A	NP_001393522.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	ENST00000298552.9	TSL:1 MANE Select	c.1142-22_1142-21delAT		intron	N/A	ENSP00000298552.3
	TSC1	ENST00000490179.4	TSL:3	c.1142-22_1142-21delAT		intron	N/A	ENSP00000495533.2
	TSC1	ENST00000493467.6	TSL:1	n.416-25_416-24delAT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00434 AC: 660 AN: 152138 Hom.: 13 Cov.: 31

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00121 AC: 300 AN: 247830 AF XY: 0.000925

Gnomad AFR exome AF: 0.0167

Gnomad AMR exome AF: 0.000638

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000449

Gnomad OTH exome AF: 0.000824

GnomAD4 exome AF: 0.000442 AC: 645 AN: 1460698 Hom.: 3 AF XY: 0.000399 AC XY: 290 AN XY: 726610

African (AFR) AF: 0.0143 AC: 479 AN: 33456

American (AMR) AF: 0.000716 AC: 32 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52928

Middle Eastern (MID) AF: 0.000769 AC: 4 AN: 5202

European-Non Finnish (NFE) AF: 0.0000576 AC: 64 AN: 1112006

Other (OTH) AF: 0.00103 AC: 62 AN: 60326

GnomAD4 genome AF: 0.00435 AC: 662 AN: 152256 Hom.: 13 Cov.: 31 AF XY: 0.00451 AC XY: 336 AN XY: 74430

African (AFR) AF: 0.0153 AC: 636 AN: 41536

American (AMR) AF: 0.00111 AC: 17 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00264 Hom.: 0

Bravo AF: 0.00477

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	-	Tuberous sclerosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs118203500; hg19: chr9-135786099;