rs7870151

Variant names:

• chr9-132906639-C-A
• rs7870151
• NM_000368.5:c.1438+92G>T

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.1438+92G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,137,450 control chromosomes in the GnomAD database, including 12,608 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (1974 hom., cov: 32)
  • Exomes 𝑓: 0.14 (10634 hom.)
• Consequence: TSC1 NM_000368.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.12
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 9-132906639-C-A is Benign according to our data. Variant chr9-132906639-C-A is described in ClinVar as [Benign]. Clinvar id is 1291082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.1438+92G>T		intron_variant	Intron 14 of 22	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.1438+92G>T		intron_variant	Intron 14 of 22	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.1438+92G>T		intron_variant	Intron 15 of 23	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23765 AN: 151878 Hom.: 1964 Cov.: 32

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.0989

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.0853

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.134

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.149

GnomAD4 exome AF: 0.143 AC: 140889 AN: 985476 Hom.: 10634 Cov.: 13 AF XY: 0.141 AC XY: 70841 AN XY: 503362

African (AFR) AF: 0.220 AC: 5167 AN: 23468

American (AMR) AF: 0.0940 AC: 3303 AN: 35132

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 3398 AN: 22562

East Asian (EAS) AF: 0.0689 AC: 2318 AN: 33662

South Asian (SAS) AF: 0.109 AC: 7738 AN: 70752

European-Finnish (FIN) AF: 0.116 AC: 5441 AN: 46952

Middle Eastern (MID) AF: 0.106 AC: 487 AN: 4580

European-Non Finnish (NFE) AF: 0.151 AC: 106655 AN: 704124

Other (OTH) AF: 0.144 AC: 6382 AN: 44244

GnomAD4 genome AF: 0.157 AC: 23805 AN: 151974 Hom.: 1974 Cov.: 32 AF XY: 0.151 AC XY: 11215 AN XY: 74274

African (AFR) AF: 0.214 AC: 8871 AN: 41394

American (AMR) AF: 0.104 AC: 1588 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 513 AN: 3472

East Asian (EAS) AF: 0.0855 AC: 442 AN: 5172

South Asian (SAS) AF: 0.106 AC: 511 AN: 4810

European-Finnish (FIN) AF: 0.117 AC: 1234 AN: 10560

Middle Eastern (MID) AF: 0.127 AC: 37 AN: 292

European-Non Finnish (NFE) AF: 0.150 AC: 10195 AN: 67968

Other (OTH) AF: 0.154 AC: 324 AN: 2110

Alfa AF: 0.165 Hom.: 374

Bravo AF: 0.159

Asia WGS AF: 0.130 AC: 452 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 21, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	8.4
DANN	Benign	0.43
PhyloP100		1.1
Mutation Taster		=100/0	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: rs7870151; hg19: chr9-135782026; COSMIC: COSV53775590; COSMIC: COSV53775590;