rs1076160

Positions:

• chr9-132900647-C-T

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.2625+68G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.479 in 1,607,722 control chromosomes in the GnomAD database, including 192,020 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (13705 hom., cov: 32)
  • Exomes 𝑓: 0.49 (178315 hom.)
• Consequence: TSC1 NM_000368.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.156

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=-0.87).
• BP6: Variant 9-132900647-C-T is Benign according to our data. Variant chr9-132900647-C-T is described in ClinVar as [Benign]. Clinvar id is 670691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132900647-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.584 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.2625+68G>A		intron_variant		ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.2625+68G>A		intron_variant		1	NM_000368.5	P4

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58803 AN: 151956 Hom.: 13705 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.492

Gnomad AMR AF: 0.426

Gnomad ASJ AF: 0.561

Gnomad EAS AF: 0.553

Gnomad SAS AF: 0.601

Gnomad FIN AF: 0.544

Gnomad MID AF: 0.404

Gnomad NFE AF: 0.483

Gnomad OTH AF: 0.398

GnomAD4 exome AF: 0.489 AC: 711944 AN: 1455648 Hom.: 178315 Cov.: 32 AF XY: 0.493 AC XY: 357077 AN XY: 724162

Gnomad4 AFR exome AF: 0.0971

Gnomad4 AMR exome AF: 0.405

Gnomad4 ASJ exome AF: 0.570

Gnomad4 EAS exome AF: 0.531

Gnomad4 SAS exome AF: 0.588

Gnomad4 FIN exome AF: 0.537

Gnomad4 NFE exome AF: 0.492

Gnomad4 OTH exome AF: 0.478

GnomAD4 genome AF: 0.387 AC: 58803 AN: 152074 Hom.: 13705 Cov.: 32 AF XY: 0.396 AC XY: 29457 AN XY: 74334

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.425

Gnomad4 ASJ AF: 0.561

Gnomad4 EAS AF: 0.552

Gnomad4 SAS AF: 0.603

Gnomad4 FIN AF: 0.544

Gnomad4 NFE AF: 0.483

Gnomad4 OTH AF: 0.399

Alfa AF: 0.467 Hom.: 22157

Bravo AF: 0.359

Asia WGS AF: 0.536 AC: 1860 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 31, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 66% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 61. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.1
DANN	Benign	0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs1076160; hg19: chr9-135776034; COSMIC: COSV53769989;