9-132900647-C-T

Variant names:

• chr9-132900647-C-T
• rs1076160
• NM_000368.5:c.2625+68G>A

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.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
• Publications: 41 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=-0.87).
• BP6: Variant 9-132900647-C-T is Benign according to our data. Variant chr9-132900647-C-T is described in ClinVar as Benign. ClinVar VariationId is 670691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.584 is higher than 0.05.

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.2625+68G>A		intron	N/A	NP_000359.1
	TSC1	NM_001406592.1		c.2625+68G>A		intron	N/A	NP_001393521.1
	TSC1	NM_001406593.1		c.2625+68G>A		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.2625+68G>A		intron	N/A	ENSP00000298552.3
	TSC1	ENST00000490179.4	TSL:3	c.2625+68G>A		intron	N/A	ENSP00000495533.2
	TSC1	ENST00000647506.1		n.3569G>A		non_coding_transcript_exon	Exon 18 of 18

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

African (AFR) AF: 0.0971 AC: 3235 AN: 33324

American (AMR) AF: 0.405 AC: 18061 AN: 44564

Ashkenazi Jewish (ASJ) AF: 0.570 AC: 14813 AN: 26002

East Asian (EAS) AF: 0.531 AC: 21018 AN: 39570

South Asian (SAS) AF: 0.588 AC: 50367 AN: 85682

European-Finnish (FIN) AF: 0.537 AC: 28483 AN: 53038

Middle Eastern (MID) AF: 0.413 AC: 1993 AN: 4822

European-Non Finnish (NFE) AF: 0.492 AC: 545300 AN: 1108610

Other (OTH) AF: 0.478 AC: 28674 AN: 60036

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

African (AFR) AF: 0.111 AC: 4619 AN: 41504

American (AMR) AF: 0.425 AC: 6507 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.561 AC: 1945 AN: 3470

East Asian (EAS) AF: 0.552 AC: 2849 AN: 5164

South Asian (SAS) AF: 0.603 AC: 2905 AN: 4820

European-Finnish (FIN) AF: 0.544 AC: 5742 AN: 10552

Middle Eastern (MID) AF: 0.394 AC: 115 AN: 292

European-Non Finnish (NFE) AF: 0.483 AC: 32831 AN: 67960

Other (OTH) AF: 0.399 AC: 842 AN: 2108

Alfa AF: 0.450 Hom.: 51744

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.1
DANN	Benign	0.68
PhyloP100		0.16
Mutation Taster		=7/93	disease causing

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

Other links and lift over

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