9-132905877-C-G

Variant names:

• chr9-132905877-C-G
• rs35478675
• NM_000368.5:c.1701G>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000368.5(TSC1):​c.1701G>C​(p.Ala567Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,459,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A567A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TSC1 NM_000368.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.224
• Publications: 4 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 9-132905877-C-G is Benign according to our data. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 237704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.224 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.1701G>C	p.Ala567Ala	synonymous_variant	Exon 15 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.1701G>C	p.Ala567Ala	synonymous_variant	Exon 15 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.1701G>C	p.Ala567Ala	synonymous_variant	Exon 16 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1459954 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 725970

African (AFR) AF: 0.00 AC: 0 AN: 33370

American (AMR) AF: 0.00 AC: 0 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1110548

Other (OTH) AF: 0.00 AC: 0 AN: 60314

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 1 Benign:2

Apr 10, 2025

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Nov 19, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.098
DANN	Benign	0.42
PhyloP100		-0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35478675; hg19: chr9-135781264;