rs7870151

Positions:

• chr9-132906639-C-A

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.1438+92G>T		intron_variant		ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.1438+92G>T		intron_variant		1	NM_000368.5	ENSP00000298552	P4

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

Gnomad4 AFR exome AF: 0.220

Gnomad4 AMR exome AF: 0.0940

Gnomad4 ASJ exome AF: 0.151

Gnomad4 EAS exome AF: 0.0689

Gnomad4 SAS exome AF: 0.109

Gnomad4 FIN exome AF: 0.116

Gnomad4 NFE exome AF: 0.151

Gnomad4 OTH exome AF: 0.144

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

Gnomad4 AFR AF: 0.214

Gnomad4 AMR AF: 0.104

Gnomad4 ASJ AF: 0.148

Gnomad4 EAS AF: 0.0855

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.150

Gnomad4 OTH AF: 0.154

Alfa AF: 0.163 Hom.: 345

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	8.4
DANN	Benign	0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs7870151; hg19: chr9-135782026; COSMIC: COSV53775590; COSMIC: COSV53775590;