9-132900647-C-T

Variant names:

• chr9-132900647-C-T
• rs1076160
• NM_000368.5:c.2625+68G>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.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 rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2625+68G>A		intron_variant	Intron 20 of 22	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.2625+68G>A		intron_variant	Intron 20 of 22	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.2625+68G>A		intron_variant	Intron 21 of 23	3		ENSP00000495533.2

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;