9-132897613-GAAAAAAAAAAAA-GAAAAAAAA

Variant names:

• chr9-132897613-GAAAA-G
• rs5901000
• NM_000368.5:c.2626-7_2626-4delTTTT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_000368.5(TSC1):​c.2626-7_2626-4delTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000256 in 1,356,086 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000096 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: TSC1 NM_000368.5 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.18
• Publications: 6 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 9-132897613-GAAAA-G is Benign according to our data. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401. Variant chr9-132897613-GAAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1692401.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2626-7_2626-4delTTTT		splice_region_variant, 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.2626-7_2626-4delTTTT		splice_region_variant, intron_variant	Intron 20 of 22	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.2626-7_2626-4delTTTT		splice_region_variant, intron_variant	Intron 21 of 23	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes AF: 0.00000960 AC: 1 AN: 104136 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000415

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000250 AC: 26 AN: 103824 AF XY: 0.000192

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000421

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000120

Gnomad FIN exome AF: 0.000633

Gnomad NFE exome AF: 0.000253

Gnomad OTH exome AF: 0.000396

GnomAD4 exome AF: 0.000276 AC: 346 AN: 1251950 Hom.: 0 AF XY: 0.000268 AC XY: 167 AN XY: 622238

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000320 AC: 9 AN: 28114

American (AMR) AF: 0.000478 AC: 13 AN: 27190

Ashkenazi Jewish (ASJ) AF: 0.000297 AC: 6 AN: 20176

East Asian (EAS) AF: 0.000283 AC: 10 AN: 35384

South Asian (SAS) AF: 0.000183 AC: 12 AN: 65592

European-Finnish (FIN) AF: 0.000848 AC: 28 AN: 33032

Middle Eastern (MID) AF: 0.000659 AC: 3 AN: 4550

European-Non Finnish (NFE) AF: 0.000243 AC: 240 AN: 986232

Other (OTH) AF: 0.000484 AC: 25 AN: 51680

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000960 AC: 1 AN: 104136 Hom.: 0 Cov.: 0 AF XY: 0.0000206 AC XY: 1 AN XY: 48580

African (AFR) AF: 0.0000415 AC: 1 AN: 24100

American (AMR) AF: 0.00 AC: 0 AN: 9916

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2992

East Asian (EAS) AF: 0.00 AC: 0 AN: 3722

South Asian (SAS) AF: 0.00 AC: 0 AN: 2988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 222

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 54480

Other (OTH) AF: 0.00 AC: 0 AN: 1374

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis syndrome Uncertain:1

Jun 28, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TSC1-related disorder Benign:1

Oct 09, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary cancer-predisposing syndrome Benign:1

Oct 07, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=98/2	polymorphism

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: rs5901000; hg19: chr9-135773000;